Evaluation and comparison of efficacy and safety of tirzepatide and semaglutide in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

BACKGROUND: As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs). RESULTS: A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs. CONCLUSION: Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.

Association of glycemic variability with death and severe consciousness disturbance among critically ill patients with cerebrovascular disease: analysis of the MIMIC-IV database.

BACKGROUND: The association of glycemic variability with severe consciousness disturbance and in-hospital all-cause mortality in critically ill patients with cerebrovascular disease (CVD) remains unclear, This study aimed to investigate the association of glycemic variability with cognitive impairment and in-hospital death. METHOD: We extracted all blood glucose measurements of patients diagnosed with CVD from the Medical Information Mart for Intensive Care IV (MIMIC-IV). Glycemic variability was defined as the coefficient of variation (CV), which was determined using the ratio of standard deviation and the mean blood glucose levels. Cox hazard regression models were applied to analyze the link between glycemic variability and outcomes. We also analyzed non-linear relationship between outcome indicators and glycemic variability using restricted cubic spline curves. RESULTS: The present study included 2967 patients diagnosed with cerebral infarction and 1842 patients diagnosed with non-traumatic cerebral hemorrhage. Log-transformed CV was significantly related to cognitive impairment and in-hospital mortality, as determined by Cox regression. Increasing log-transformed CV was approximately linearly with the risk of cognitive impairment and in-hospital mortality. CONCLUSION: High glycemic variability was found to be an independent risk factor for severe cognitive decline and in-hospital mortality in critically ill patients with CVD. Our study indicated that enhancing stability of glycemic variability may reduced adverse outcomes in patients with severe CVD.

Association between triglyceride-glucose index and all-cause mortality in critically ill patients with ischemic stroke: analysis of the MIMIC-IV database.

BACKGROUND: The triglyceride-glucose (TyG) index was significantly associated with insulin resistance (IR). Several studies have validated the effect of TyG index on cerebrovascular disease. However, the value of TyG index in patients with severe stroke requiring ICU admission remains unclear. The aim of this study was to investigate the association between the TyG index and clinical prognosis of critically ill patients with ischemic stroke (IS). METHODS: This study identified patients with severe IS requiring ICU admission from the Medical Information Mart for Intensive Care (MIMIC-IV) database, and divided them into quartiles based on TyG index level. The outcomes included in-hospital mortality and ICU mortality. The association between the TyG index and clinical outcomes in critically ill patients with IS was elucidated using Cox proportional hazards regression analysis and restricted cubic splines. RESULTS: A total of 733 patients (55.8% male) were enrolled. The hospital mortality and intensive care unit (ICU) mortality reached 19.0% and 14.9%, respectively. Multivariate Cox proportional hazards analysis showed that the elevated TyG index was significantly related to all-cause death. After confounders adjusting, patients with an elevated TyG index had a significant association with hospital mortality (adjusted hazard ratio, 1.371; 95% confidence interval, 1.053-1.784; P = 0.013) and ICU mortality (adjusted hazard ratio, 1.653; 95% confidence interval, 1.244-2.197; P = 0.001). Restricted cubic splines revealed that a progressively increasing risk of all-cause mortality was related to an elevated TyG index. CONCLUSION: The TyG index has a significant association with hospital and ICU all-cause death in critically ill patients with IS. This finding demonstrates that the TyG index might be useful in identifying patients with IS at high risk of all-cause death.

Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway.

Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.

Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 µg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.

Inhibition of Human UDP-Glucuronosyltransferases1A1-Mediated Bilirubin Glucuronidation by the Popular Flavonoids Baicalein, Baicalin, and Hyperoside Is Responsible for Herb (Shuang-Huang-Lian)-Induced Jaundice.

Bilirubin-related adverse drug reactions (ADRs) or malady (e.g., jaundice) induced by some herbs rich in certain flavonoids have been widely reported. However, the causes and mechanisms of the ADRs are not well understood. The aim of this paper was to explore the mechanism of Shuang-huang-lian (SHL) injections and its major constituents-induced jaundice via inhibiting human UDP-glucuronosyltransferases1A1 (hUGT1A1)-mediated bilirubin glucuronidation. The inhibitory effects of SHL and its major constituents in the herbal medicine, including baicalein (BAI), baicalin (BA), and hyperoside (HYP), on bilirubin glucuroBBREVInidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides [i.e., mono-glucuronide 1 (BMG1), BMG2, and bilirubin diglucuronide] displayed significant differences (P < 0.05). Specifically, the formation of BMGs was favored regardless of whether an inhibitor was absent or present. SHL, BAI, BA, and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC50 values against total bilirubin glucuronidation were in the range of (7.69 ± 0.94)-(37.09 ± 2.03) µg/ml, (4.51 ± 0.27)-(20.84 ± 1.99) µM, (22.36 ± 5.74)-(41.35 ± 2.40) µM, and (15.16 ± 1.12)-(42.80 ± 2.63) µM for SHL, BAI, BA, and HYP, respectively. Both inhibition kinetics assays and molecular docking simulations suggested that SHL, BAI, BA, and HYP significantly inhibited hUGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibition. Collectively, some naturally occurring flavonoids (BAI, BA, and HYP) in SHL have been identified as the inhibitors against hUGT1A1-mediated bilirubin glucuronidation, which well explains the bilirubin-related ADRs or malady triggered by SHL in clinical settings. SIGNIFICANCE STATEMENT: Herbal products and their components (e.g., flavonoids), which been widely used across the entire world, may cause liver injury. As a commonly used herbal products rich in flavonoids, SHL injections easily lead to symptoms of liver injury (e.g., jaundice) owing to significant inhibition of hUGT1A1-mediated bilirubin glucuronidation by its flavonoid components (i.e., baicalein, baicalin, and hyperoside). Herb-induced bilirubin-related ADRs and the associated clinical significance should be seriously considered.

A new Eimeria coccidian species (Apicomplexa: Eimeriidae) from Père David's deer (Elaphurus davidianus Milne-Edwards, 1866) in Dafeng Milu National Nature Reserve in Jiangsu Province, eastern China.

BACKGROUND: Eimeria coccidiosis is a significant intestinal parasitic disease, which can lead to weight loss, disease and even death of many animals. At present, there is no information about the prevalence of Eimeria among the world's endangered species of Père David's deer (Elaphurus davidianus). Therefore, the purpose of this study is to identify an unknown Eimeria genus in the Père David's deer in Dafeng Milu National Nature Reserve, China. RESULTS: A new Eimeria species is described from Père David's deer. Sporulated oocysts (n = 54) are pyriform, with a rough, yellowish brown, 2-layered oocyst wall (2.5 µm thick). A numerous small granules are dispersed randomly on the wall. Oocysts measured 41.2 (39.2-42.8) µm × 29.5 (27.9-30.5) µm, oocyst length/width (L/W) ratio, 1.4. Oocyst residuum, a polar granule and a polar cap are absent. The micropyle (3.5 µm wide) is present. Sporocysts are spindle shaped, 18.2 (16.5-20.0) µm × 10.5 (9.8-11.9) µm, sporocyst L/W ratio, 1.7 (1.5-1.9). A thin convex Stieda body is present and the sporocyst residuum is composed of numerous small granules less than 2.0 µm in diameter dispersed randomly. Each sporocyst contained 2 comma-shaped sporozoites in head-to-tail arrangement. A nucleus is located immediately anterior to the posterior, strong refractive and subspherical refractile body (~ 8 µm). Molecular analysis was conducted at the 18S, ITS-1 and COI loci. CONCLUSION: Based on the morphological and molecular data, this isolate is a new species of coccidian parasite, which is named Eimeria davidianusi after its host, the Père David's deer (Elaphurus davidianus).

Prediction of Patient Survival with Psoas Muscle Density Following Transjugular Intrahepatic Portosystemic Shunts: A Retrospective Cohort Study.

BACKGROUND Psoas muscle density (PMD) as a nutritional indicator is a tool to evaluate sarcopenia, which is commonly diagnosed in patients with liver cirrhosis. However, there are limited data on its role in patients who have received a transjugular intrahepatic portosystemic shunt (TIPS). We aimed to determine the utility of PMD in predicting mortality of patients with TIPS implantation and to compare the clinical value of PMD, Child-Pugh score, model for end-stage liver disease (MELD) score, and MELD paired with serum sodium measurement (MELD-Na) score in predicting post-TIPS survival in 1 year. MATERIAL AND METHODS This retrospective study included 273 patients who met the criteria for study inclusion. All participants underwent computed tomography (CT) scans, Child-Pugh score evaluation, MELD-Na scoring, and MELD scoring. Post-TIPS survival time was estimated using the Kaplan-Meier survival curve. The prognostic values of scoring models such as the Child-Pugh score, MELD, MELD-Na, and PMD were evaluated using receiver operating characteristic curves. RESULTS During the 1-year follow-up period, 31 of 273 (11.36%) post-TIPS patients died. Multivariate analysis identified PMD as an independent protective factor. PMD showed a good ability to predict the occurrence of an endpoint within 1 year after TIPS. The area under the receiver operating characteristic curves for PMD, Child-Pugh score, MELD score, and MELD-Na for predicting mortality were, respectively, 0.72 (95% confidence interval [CI]: 0.663-0.773), 0.59 (95% CI: 0.531-0.651), 0.60 (95% CI: 0.535-0.655), and 0.58 (95% CI: 0.487-0.608). CONCLUSIONS PMD has appreciable clinical value for predicting the mortality of patients with TIPS implantation. In addition, PMD is superior to established scoring systems for identifying high-risk patients with a poor prognosis.

Investigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: A physiologically based pharmacokinetic/pharmacodynamic analysis.

AIMS: Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the combination of ritonavir and nifedipine can potentially cause drug-drug interactions. This study provides guidance on nifedipine treatment during and after coadministration with ritonavir-containing regimens, using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. Various nifedipine regimens were investigated when coadministered with or without ritonavir. RESULTS: PBPK/PD models for 3 formulations of nifedipine were successfully established. The predicted maximum concentration (Cmax ), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSION: Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.

First report on the prevalence of Fasciola hepatica in the endangered Père David's deer (Elaphurus davidianus) in China.

BACKGROUND: Fasciola hepatica is an important zoonotic parasite that causes fasciolosis in a broad range of animals. No information is available about the prevalence of F. hepatica in Père David's deer (Elaphurus davidianus), an endangered species in the world. Therefore, the purpose of the study was to evaluate the prevalence of fasciolosis in Père David's deer in the Dafeng Elk National Natural Reserve, Jiangsu province, China. RESULTS: In this study, 142 fecal samples from Père David's deer were analyzed for F. hepatica by microscopy and nest-PCR. Only one sample was positive for F. hepatica according to microscopy examination, while 18 of 142 (12.68, 95%CI: 2.841-22.45%) samples were positive for F. hepatica according to nest-PCR results. CONCLUSIONS: This is the first report of prevalence of F. hepatica in Père David's deer. The prevalence data indicated that F. hepatica was also present in this endangered animal, which may cause a potential threat to this precious species.

Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave's disease: a metabolomic approach.

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

Prognostic Value of Acute-On-Chronic Liver Failure (ACLF) Score in Critically Ill Patients with Cirrhosis and ACLF.

BACKGROUND In the intensive care unit (ICU), critically ill patients with cirrhosis and acute-on-chronic liver failure (ACLF) continue to have high mortality rates. The AARC ACLF score is a simple, newly-developed score based on Asian ACLF patients, which performs well in prognosis. The present study attempted to verify the prognostic ability of AARC ACLF in non-Asian critically ill patients with cirrhosis and ACLF. MATERIAL AND METHODS We enrolled 786 patients. Relevant clinical data were collected within 24 h after admission to compare the differences between survivors and non-survivors, and all the patients were followed up for at least 180 days. RESULTS The 28-day, 90-day, and 180-day mortality rates were 28.9% (227/786), 36.4% (286/786), and 40.3% (317/786), respectively. Multivariate Cox regression analysis showed that AARC ACLF score (HR: 1.375, 95% CI: 1.247-1.516, P<0.001) was an independent predictive factor of 28-day mortality, and the AUROC of the predictive ability in 28-day mortality of the AARC ACLF score was 0.754. In addition, the AARC ACLF score was regraded into 3 classes (low risk: AARC ACLF <9, intermediate risk: 9≤ AARC ACLF <12, and high risk: AARC ACLF ≥12). The AARC ACLF score can be used for dynamic assessment by retest at days 4-7. CONCLUSIONS The AARC ACLF score has a good predictive value for 28-day, 90-day, and 180-day mortality in non-Asian critically ill patients with cirrhosis and ACLF, which is not inferior to CLIF-C ACLFsLact and other models. It is easy to use at bedside, and it is dynamic and reliable.

Association of Hepatic Nuclear Factor 4 Alpha Gene Polymorphisms With Free Imatinib Plasma Levels and Adverse Reactions in Chinese Gastrointestinal Stromal Tumor Patients.

BACKGROUND: As the first-line treatment of gastrointestinal stromal tumor (GIST), the pharmacokinetic and pharmacodynamic of imatinib (IM) were characterized by marked interindividual variability. Pharmacogenetics of IM involved metabolic enzymes and transporters have been extensively reported, but the results remained inconsistent. This study investigated the effect of genetic variants in hepatocyte nuclear factor 4 alpha (HNF4α, encoded by gene NR2A1), a pivotal transcriptional regulator of drug disposition genes, on dose-adjusted IM-free plasma levels and related adverse reactions in Chinese GIST patients. METHODS: Five common polymorphisms of NR2A1 (rs3818247, rs1884613, rs2071197, rs2425640, and rs736824) were genotyped in 70 Chinese GIST patients who had been administered IM 300-600 mg/d. The free IM trough plasma levels were determined based on a method of ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry. RESULTS: There were wide interpatient variations in free plasma levels of IM (range, 9.50-67.50 ng/mL), in which significant sex differences were observed (P < 0.01). The dose-adjusted IM-free plasma levels showed a significant negative correlation with body surface area (r = -0.302, P = 0.012). Although there were no significant effects of NR2A1 polymorphisms on dose-adjusted IM-free plasma levels among the study population, polymorphism in rs736824 was found to be significantly associated with dose-adjusted IM-free plasma levels in male subjects (P = 0.031). For the IM-related adverse reaction, polymorphisms in rs3818247 were found to be significantly associated with periorbital edema (P = 0.032). In addition, no significant correlations were found between IM-free plasma levels and IM-related adverse reactions, except for the correlation of IM-free plasma levels with periorbital edema among male patients (P = 0.013). CONCLUSIONS: The research demonstrated that NR2A1 polymorphisms may act as contributors of IM pharmacokinetics and responses in Chinese GIST patients. This represents an attractive opportunity for IM therapy optimization, worth testing in clinical trials.

Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients.

PURPOSE: The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response. METHODS: A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing. RESULTS: We identified a DNA methylation predictor (P = 0.006-0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057-1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44). CONCLUSIONS: Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.

Novel in vitro dynamic metabolic system for predicting the human pharmacokinetics of tolbutamide.

Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide. Human liver microsomes (HLMs) encapsulated in a F127'-Acr-Bis hydrogel (FAB hydrogel) were placed in the incubation system. A microdialysis sampling technique was used to monitor the metabolic behavior of tolbutamide in hydrogels. The measured results in the system were used to fit the in vitro intrinsic clearance of tolbutamide with a mathematical model. Then, a PBPK model that integrated the corresponding in vitro intrinsic clearance was developed to verify the system. Compared to the traditional incubation method, reasonable PK profiles and the in vivo clearance of tolbutamide could be predicted by integrating the intrinsic clearance of tolbutamide obtained from the Bio-PK metabolic system into the PBPK model. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration (Tmax) and in vivo clearance were consistent with the clinically observed data. This novel in vitro dynamic metabolic system can compensate for some limitations of traditional incubation methods; it may provide a new method for screening compounds and predicting pharmacokinetics in the early stages, supporting the development of compounds.

Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide.

1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20 mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software. 3. The predicted in vivo clearance of CP at concentrations of 5, 10 and 20 mM was 11.36, 10.12 and 10.68 mL/min/kg, respectively, within two-fold differences compared with the reported 11.1 mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced. 4. This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.

Inhibition of Human UGT1A1-Mediated Bilirubin Glucuronidation by Polyphenolic Acids Impact Safety of Popular Salvianolic Acid A/B-Containing Drugs and Herbal Products.

Bilirubin-related adverse reactions (ADR, e.g., jaundice and hyperbilirubinemia) induced by herbs rich in certain polyphenolic acids are widely reported. However, the causes and the mechanisms underlying these ADR are not well understood. The purpose of this article is to determine the mechanism by which certain polyphenolic acids inhibit UGT1A1-mediated bilirubin glucuronidation, leading to jaundice or hyperbilirubinemia. We investigated in vitro inhibitory effects on bilirubin glucuronidation of salvianolic acid A (SAA), salvianolic acid B (SAB), danshensu (DSS), protocatechuic aldehyde (PA), and rosmarinic acid (RA), as well as two Salvia miltiorrhiza injections (DSI and CDI) rich in polyphenolic acids. The results showed that average formation rates of three bilirubin glucuronides displayed a significant difference (p < 0.05) and the formation of monoglucuronide was favored regardless if an inhibitor was present or not. SAA, SAB, DSI, and CDI, but not DSS, PA, and RA, significantly inhibited human UGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibitory mechanism. Average IC50 values of SAA, SAB, DSI, and CDI-mediated inhibition of bilirubin glucuronidation were bilirubin concentration-dependent, and their values (against total bilirubin glucuronidation) were in the range 0.44 ± 0.02 to 0.86 ± 0.04 µg/mL (for SAA), 4.22 ± 0.30 to 12.50 ± 0.93 µg/mL (for SAB), 9.29 ± 0.76 to 18.82 ± 0.63 µg/mL (for DSI), and 9.18 ± 2.00 to 22.36 ± 1.39 µg/mL (for CDI), respectively. In conclusion, SAA and its analog SAB are the main ingredients responsible for inhibition of bilirubin glucuronidation by DSI and CDI, whose use is associated with many high bilirubin-related ADR.

Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients.

Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.

Application of a New Dynamic Model to Predict the In Vitro Intrinsic Clearance of Tolbutamide Using Rat Microsomes Encapsulated in a Fab Hydrogel.

Currently used in vitro models for estimating liver metabolism do not take into account the physiologic structure and blood circulation process of liver tissue. The Bio-PK metabolic system was established as an alternative approach to determine the in vitro intrinsic clearance of the model drug tolbutamide. The system contained a peristaltic pump, recirculating pipeline, reaction chamber, and rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogel. The metabolism of tolbutamide at initial concentrations of 100, 150, and 200 µM was measured in both the FAB hydrogel and the circular medium. The data from the FAB hydrogel and the circular medium were fitted to a mathematical model to obtain the predicted intrinsic clearance of tolbutamide after different periods of preincubation. The in vitro clearance value for tolbutamide was incorporated into Simcyp software and used to predict both the in vivo clearance value and the dynamic process of elimination. The predicted in vivo clearance of tolbutamide was 0.107, 0.087, and 0.095 L/h/kg for i.v. injection and 0.113, 0.095, and 0.107 L/h/kg for oral administration. Compared with the reported in vivo clearance of 0.09 L/h/kg (i.v.) and 0.10 L/h/kg (oral), all the predicted values differed by less than twofold. Thus, the Bio-PK metabolic system is a reliable and general in vitro model, characterized by three-dimensional structured RLM and circulation and perfusion processes for predicting the in vivo intrinsic clearance of low-extraction compounds, making the system more analogous with the rat in terms of both morphology and physiology.

Sulfur Dioxide Capture by Heterogeneous Oxidation on Hydroxylated Manganese Dioxide.

Here we demonstrate that sulfur dioxide (SO2) is efficiently captured via heterogeneous oxidation into sulfate on the surface of hydroxylated manganese dioxide (MnO2). Lab-scale activity tests in a fluidized bed reactor showed that the removal efficiency for a simulated flue gas containing 5000 mg·Nm(-3) SO2 could reach nearly 100% with a GHSV (gas hourly space velocity) of 10000 h(-1). The mechanism was investigated using a combination of experimental characterizations and theoretical calculations. It was found that formation of surface bound sulfate proceeds via association of SO2 with terminal hydroxyls. Both H2O and O2 are essential for the generation of reactive terminal hydroxyls, and the indirect role of O2 in heterogeneous SO2 oxidation at low temperature was also revealed. We propose that the high reactivity of terminal hydroxyls is attributed to the proper surface configuration of MnO2 to adsorb water with degenerate energies for associative and dissociative states, and maintain rapid proton dynamics. Viability analyses suggest that the desulfurization method that is based on such a direct oxidation reaction at the gas/solid interface represents a promising approach for SO2 capture.