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Chengxiao Fu,1,2,* Qi Pei,3,* Wu Liang,4 Bo Yang,2 Wei Li,5 Jun Liu,5 Hongyi Tan,1,4 Chengxian Guo,1,4 Hao Zhang,5 Guoping Yang1,4 1Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, People’s Republic of China; 3Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Research Center of Drug Clinical Evaluation of Central South University, Changsha, People’s Republic of China; 5Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoping Yang; Hao Zhang, Email ygp9880@126.com; zhanghaoliaoqing@163.comPurpose: Parathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear.Methods: This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model.Results: The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation.Conclusion: This study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.Keywords: chronic kidney disease, parathyroid hormone, CYP3A, population pharmacokinetic, nifedipine

A 3D N-doped ordered honeycomb nanostructure with Pt active sites (Pt/N-OHC), precisely controlled by the self-assembly of a block copolymer, provides a four-electron (4-e) transfer pathway and improved activity for the oxygen reduction reaction (ORR).

Chlamydia psittaci pneumonia has atypical clinical manifestations and the diagnosis may be missed by traditional methods of microbiological diagnosis.Twelve cases of Chlamydia psittaci pneumonia diagnosed by metagenomic next-generation sequencing (mNGS) in Huizhou Central People's Hospital in China between January 2020 and August 2021 were reviewed and analyzed, retrospectively, using hospital records, the clinical characteristics, treatment, and prognosis.Ten of the 12 cases (83%) were associated with a definite history of bird/poultry contact. Common symptoms included high fever, cough, fatigue, anorexia (12/12, 100%), dyspnea (11/12, 92%), and changes in the level of consciousness and headache (5/12, 42%). There was a marked increase in C-reactive protein and D-dimer levels, but white blood cells and neutrophils were normal or slightly increased. Nine patients (75%) had liver enzyme abnormalities, and six (50%) had cardiac insufficiency and myocardial injury. There was no correlation between the mNGS sequence number of Chlamydia psittaci and the pneumonia severity. The chest imaging manifestations were mainly large areas of consolidation, predominantly in the lower lung lobes. Monotherapies or combinations of doxycycline, moxifloxacin/levofloxacin, and azithromycin were effective for treating Chlamydia psittaci pneumonia.The use of mNGS increases the probability of diagnosing Chlamydia psittaci pneumonia, and good prognosis can be achieved with timely use of appropriate antibiotics.

Several population pharmacokinetics (popPK) models for polymyxin B have been constructed to optimize therapeutic regimens. However, their predictive performance remains unclear when extrapolated to different clinical centers. Therefore, this study aimed to evaluate the predictive ability of polymyxin B popPK models. A literature search was conducted, and the predictive performance was determined for each selected model using an independent dataset of 20 patients (92 concentrations) from the Third Xiangya Hospital. Prediction- and simulation-based diagnostics were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Eight published studies were evaluated. In prediction-based diagnostics, the prediction error within ± 30% was over 50% in two models. In simulation-based diagnostics, the prediction- and variability-corrected visual predictive check (pvcVPC) showed satisfactory predictivity in three models, while the normalized prediction distribution error (NPDE) tests indicated model misspecification in all models. Bayesian forecasting demonstrated a substantially improvement in the model predictability even with one prior observation. Not all published models were satisfactory in prediction- and simulation-based diagnostics; however, Bayesian forecasting improved the predictability considerably with priors, which can be applied to guide polymyxin B dosing recommendations and adjustments for clinicians.

Background Delirium, a disorder of consciousness, often occurs for a period of time during hospitalisation. It is characterised by a disturbance of attention or awareness. Hyperactive delirium may lead to accidental removal of medical equipment, while hypoactive delirium may inhibit patients from participating in nursing interventions, medical treatment, and physical therapy. However, there are limited relevant studies of the strain of care of nurses in China when caring for patients with delirium. This study, thus, aimed to investigate the subjective level of the strain of care experienced by pulmonary and critical care nurses when caring for patients with delirium. Methods This was a descriptive, cross-sectional study. A survey was conducted with 100 nurses in the Chinese pulmonary and critical care medical (PCCM) department in 2018. The Strain of Care for Delirium Index (SCDI) was used to measure nurses’ strain of care. Participants were instructed to rate the degree of perceived difficulty in managing patients who displayed the behaviours listed in the SCDI, on a scale from 1 (quite easy) to 4 (very difficult). The mean ± standard deviation (SD) scores of the ranked difficulty scores were calculated. Results In our sample, 47 % of the nurses had received delirium-related training previously. The three wards with the highest strain of care scores when caring for patients with delirium were the chronic obstructive pulmonary disease ward (3.29 ± 0.72), interstitial lung disease ward (3.11 ± 1.31), and respiratory intensive care unit (3.02 ± 0.78). The three types of patient behaviours associated with the highest degree of nursing strain of care were being uncooperative and difficult to manage (3.37 ± 0.84), pulling out tubes and tearing out dressings (3.33 ± 0.98), and irritability (3.22 ± 0.95). Conclusions This study is the first to focus on nurses’ subjective strain of care when caring for patients with delirium in PCCM departments in China. The findings suggest the need to pay more attention to the working status of Chinese nurses. Further trials with large samples assessing relevant outcomes of patients with delirium are warranted.

Highlights • Human adenovirus-55 in a single patient had strong transmission potential in ICU • This infections event involving more than 20 medical staff members in adult ICU • Contact with patient, lack of hand hygiene or gloving adherence were risk factors, Rationale In 2019, a small HAdV55-associated outbreak of adenovirus infection occurred among the intensive care unit (ICU) staff in Xiangya Hospital of Central South University in Hunan Province, China during the treatment of a patient. Objective To investigate the characteristics of a nosocomial adenovirus outbreak in the ICU. Methods We evaluated all the patients treated and the medical staff working in the ICU from August 1 to September 4, 2019. We further performed an epidemiological and molecular analysis for this outbreak from patient to healthcare workers and between healthcare workers. After the outbreak, we adopted exposure prevention and droplet prevention measures based on standard precautions. Measurements and Main Results Between August 1 and August 27, 2019, 27 cases of human adenovirus cross-infection were reported in our institution. Among the cases, 11 were doctors (41%), 11 were nurses (41%), three were respiratory therapists (11%), and two were caregivers (7%). The attack rate was 28.4% and the fatality rate was 0. The results showed that contact with the index case, lack of hand hygiene or gloving adherence was a risk factor for infection after adenovirus exposure. After taking specific precautions, no new cases of infection have appeared since August 27. Conclusions Our results show that HAdV55 in a single patient had strong transmission potential in an intensive care unit with adequate facilities and standardized operation. We provide convincing evidence indicating that attention could be highlighted the role of standard and specific precautions in controlling the spread of adenovirus in ICUs.

In order to investigate the effects of the substitution position on the photovoltaic performance of donor polymers, two benzothiophene ring substituted benzo(1,2-b:4,5-b′)dithiophene (BDT)-based conjugated polymers (PBDTBTs-BDD and PBDTTBs-BDD) are designed and synthesized. The variation in the substitution position has small influences on the photophysical properties but has a great effect on the intramolecular π–π stack structure, charge transport and photovoltaic properties. PBDTBTs-BDD (with the 6-position of the benzothiophene substituent) exhibited a smaller π–π stacking distance of 3.67 A compared to 4.11 A seen for PBDTTBs-BDD (with the 2-position of the benzothiophene substituent). And the charge mobilities of PBDTBTs-BDD-based devices are higher and more balanced than those of PBDTTBs-BDD-based devices, which are highly beneficial for reducing recombination of free carriers and then lead to a higher short-circuit current density (JSC) and fill factor (FF) of devices. With ITIC or Y6 as non-fullerene acceptors, PBDTBTs-BDD-based devices exhibit power conversion efficiencies (PCE) of 7.76% and 12.07%, respectively, which are higher than those of PBDTTBs-BDD-based devices (5.04% and 5.81%). This work demonstrates that the photovoltaic properties of donor polymers can be highly tunable through slight modifications of their side chain structures.

To analyze the clinical characteristics of Chlamydia psittaci pneumonia and to investigate the correlation between serum inflammatory biomarkers and severity of the disease.Sixteen patients with Chlamydia psittaci pneumonia admitted to the Huizhou Municipal Central Hospital from January 2020 to July 2021 were selected as the study subjects, including 10 severe cases and 6 mild cases. Clinical data were collected and analyzed, such as baseline characteristics, clinical symptoms, laboratory inspection and chest imaging manifestations.(1) Thirteen Chlamydia psittaci pneumonia were associated with a definite bird or poultry contact history. Common symptoms included high fever, chill, cough, fatigue, and anorexia (16 cases), dyspnoea (12 cases), and other systemic symptoms. (2) Laboratory test results showed normal white blood cell count (WBC, 10 cases), decreased lymphocyte count (LYM, 13 cases), increased high sensitive C-reactive protein (hs-CRP, 16 cases), D-dimer (15 cases), lactate dehydrogenase (LDH, 13 cases), aspartate aminotransferase (AST, 16 cases) and alanine aminotransferase (ALT, 12 cases) levels, however, the albumin (Alb, 15 cases) lever was decreased. The numbers of CD3Chlamydia psittaci pneumonia is mainly associated with a bird or poultry contact history. The clinical manifestations usually present high fever, dyspnea, normal or slightly increased leucocytes, and lung consolidation. The levels of LYM, D-dimer, IL-2, IL-6 and IL-10 in serum are expected to predict the severity of the Chlamydia psittaci pneumonia.

Two acceptor-donor1-donor2-donor1-acceptor (A-D1-D2-D1-A)-type narrow bandgap small molecules BDT(IDT-IC)2 and BDT(IDT-IC-2F)2 with indacenodithiophene–benzodithiophene-indacenodithiophene (BDT-(IDT)2) as donating cores and 2-(3-oxo-2,3-dihydroinden-1-ylidene) malononitrile (IC) or 2-(5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene) malononitrile (2FIC) as end groups, have been synthesized and investigated as non-fullerene acceptors in solution-processed polymer solar cells (PSCs). The optical bandgaps of BDT(IDT-IC)2 and BDT(IDT-IC-2F)2 are 1.59 eV and 1.54 eV, respectively. Using PBDB-T as donor, the power conversion efficiencies (PCEs) of 4.98% and 6.21% are achieved by PSCs based on BDT(IDT-IC)2 and BDT(IDT-IC-2F)2, respectively.

Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P

Lung adenocarcinoma, which is the most common non-small cell lung cancer, is the leading cause of death from cancer worldwide. Epithelial cell transforming sequence 2 (ECT2) is frequently upregulated and acts as an oncogene in various human cancers. In addition, ECT2 was reported to be upregulated in early stage lung adenocarcinoma. However, the detailed role of ECT2 in mediating the malignant phenotypes of lung adenocarcinoma cells has not previously been elucidated. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to examine ECT2 mRNA and protein expression levels, respectively. MTT, wound healing and Transwell assays were conducted to determine cell proliferation, migration and invasion abilities, respectively. In the present study, ECT2 was significantly upregulated in lung adenocarcinoma cell lines (H650, EKVX, HCC4006, HCC827, HCC2935, Hop62 and A549), as compared with a normal lung epithelial cell line (BEAS-2B). Moreover, knockdown of ECT2, induced by transfection with ECT2 siRNA, significantly inhibited the proliferation of lung adenocarcinoma A549 cells, whereas overexpression of ECT2 enhanced A549 cell proliferation. Furthermore, knockdown of ECT2 expression suppressed the migration and invasion of A549 cells, whereas overexpression of ECT2 enhanced the migration and invasion abilities of A549 cells. Notably, inhibition of ECT2 also suppressed the expression levels of N-cadherin and vimentin, whereas it enhanced the expression level of E-cadherin, indicating that ECT2 is associated with the epithelial-mesenchymal transition in A549 cells. On the contrary, overexpression of ECT2 enhanced the expression levels of N-cadherin and vimentin, whereas it reduced the expression level of E-cadherin in A549 cells. In conclusion, the results of the present study suggest that ECT2 has an oncogenic role in lung adenocarcinoma cells. Therefore, ECT2 may be a potential novel target for the treatment of lung adenocarcinoma.

Background: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. Methods: We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. Results: A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1–10.2]; P =0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1–24.4]). The incidence of adverse events was low in both groups. Conclusions: The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02211326.

Objective Imrecoxib is a new moderately selective cyclooxygenase-2 (COX-2) inhibitor. A previous study has shown that drug exposure differs significantly in renally impaired patients. We aim to describe the population pharmacokinetics (PPK) of imrecoxib (M0) and its two metabolites (M1, M2) to provide a theoretical basis for investigating imrecoxib doses for renally impaired patients. Methods Using PPK analysis, 24 patients with 257 different plasma concentrations were studied. Of these, 12 had severe renal impairment and 12 had normal renal function. The dose regimen was simulated based on the final model to compare the ratio (Cu,ss/IC50) of the average unbound concentration at steady state (Cu,ss) to the half-maximal inhibitory concentration (IC50) of COX-2. Results Imrecoxib and its metabolite concentrations were satisfactorily described by a two-compartment with first-order transit absorption model for imrecoxib and a one-compartment model for its metabolites. Renal function was a significant binary covariate. Scenarios of ‘75 mg q12h’ and ‘50 mg q8h’ in renally impaired patients had similar Cu,ss/IC50 values with a ‘100 mg q12h’ regimen in subjects with normal renal function. Conclusion A PPK model of imrecoxib and its two metabolites is presented. The renal insufficiency regimen should be reduced to ‘75 mg q12h’ or ‘50 mg q8h’.

Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema. Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1β, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1β and TGF-β1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1β maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1β in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1β secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients.

// Haitao Li 1 , Xiaoting Zhou 2 , Hongyi Tan 3 , Yongbin Hu 4 , Lemeng Zhang 5 , Shuai Liu 1 , Minhui Dai 1 , Yi Li 1 , Qian Li 1 , Zhi Mao 1 , Pinhua Pan 1 , Xiaoli Su 1 and Chengpin Hu 1 1 Department of Pulmonary and Critical Care Medicine, Key Site of National Clinical Research Centre for Respiratory Disease, Xiangya Hospital, Central South University, Changsha 410008, China 2 Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China 3 Department of Respiratory Medicine, Changsha Central Hospital, Changsha, 410004, China 4 Department of Pathological Medicine, Xiangya Hospital, Central South University, Changsha 410008, China 5 Department of Thoracic Medicine, Hunan Cancer Hospital, Affiliated to Xiangya Medical School, Central South University, Changsha, 410013, China Correspondence to: Pinhua Pan, email: pinhuapan668@126.com Keywords: neutrophil extracellular traps(NETs); acid-aspiration; acute lung injury(ALI); acute respiratory distress syndrome(ARDS) Received: July 28, 2017 Accepted: October 30, 2017 Published: November 28, 2017 ABSTRACT Background: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a manifestation of systemic inflammation in the lungs, but the factors that trigger inflammation in ALI/ARDS are unclear. We hypothesized that neutrophil extracellular traps (NETs) contribute to the pathogenesis of acid aspiration-induced ALI/ARDS. Results: Analysis of bronchial aspirates from ARDS patients showed that NETs were significantly correlated with the degree of ARDS (r = –0.5846, p = 0.0359). NETs in bronchoalveolar lavage fluid of acid-aspiration mice were significantly higher (141.6 ± 23.08) at 3 h after injury than those in the sham group (1234 ± 101.9; p = 0.003, n = 5 per group). Exogenous NETs aggravated lung injury, while alvelestat and DNase markedly attenuated the intensity of ARDS. Materials and Methods: We investigated whether NETs are involved in the severity of gastric aspiration-induced ARDS. Then, a hydrochloric acid aspiration-induced ALI murine model was used to assess whether NETs are pathogenic and whether targeting NETs is protective. Exogenous NETs were administered to mice. Alvelestat can inhibit neutrophil elastase (NE), which serves an important role in NET formation, so we investigated whether alvelestat could protect against ALI in cell and mouse models. Conclusions: NETs may contribute to ALI/ARDS by promoting tissue damage and systemic inflammation. Targeting NETs by alvelestat may be a potential therapeutic strategy.

Catalytic hydrogen evolution plays a significant role in hydrogen production and utilization. The combinative desorption of hydrogen (Tafel step, i.e., 2H*→H2) from metal catalysts has been extensively reported as the rate-determining step. However, a full atomic-level understanding on how the H-Metal binding strength affects on the elementary Tafel steps is still lacking. In the current study, H2 evolution over Pd catalysts was investigated by combining theoretical and experimental techniques. Density functional theory calculations revealed that H2 evolution was governed by either the combination barriers of 2H* or the desorption barriers of molecular H2 from the surface of the palladium catalyst, which was strongly dependent on the size of Pd particles: the rate-limiting step of H2 evolution for large nanoparticles (NPs) is diffusive combination of H* across the metal surface, while both 2H* combination and H2 desorption are difficult for subnanometer-sized Pd clusters. By tuning the combined effect of H adatom combination and H2 desorption, a highly performance Pd catalyst for hydrogen evolution both for temperature-programmed palladium hydride decomposition and catalytic dehydrogenation of formate was designed and synthesized. TiO2-supported Pd NPs that were 2 nm in size exhibited excellent activity for formate dehydrogenation with an TOF value that was as high as 2184 h−1 at 298 K.

Acinetobacter baumannii is an important pathogen that primarily causes hospital-acquired pneumonia. The present study sought to investigate whether small protein A (SmpA) and phospholipase D (PLD) are potential candidates for protective immunity against infection with A. baumannii. Mice immunized with the fusion proteins histidine (His)‑SmpA and His‑PLD exhibited a specific immunoglobulin G response. In a pneumonia model, active and passive immunization against SmpA and PLD protected mice from A. baumannii infection. The protection was demonstrated by a markedly improved survival rate, and reduced pulmonary bacterial load, infiltration and cytokine levels in the broncho‑alveolar lavage fluid and the serum, although a combination of the two antigens did not provide improved protection compared with immunization with the individual antigens alone. In conclusion, it was identified that SmpA and PLD are highly immunogenic proteins, and potential antigen candidates for the development of effective vaccines or to prepare antisera to mitigate A. baumannii infection.

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers. Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30-300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel. Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

Telmisartan is an angiotensin receptor blocker used for the treatment of hypertension. The effects of gender and uridine diphosphate-glycosytransferase 1A1 (UGT1A1) genetic polymorphisms (rs4124874, rs4148323, and rs6742078) on telmisartan plasma concentration and blood pressure in Chinese patients with hypertension have been reported previously. In this study, we aimed to develop a population pharmacokinetic (PopPK) model to quantify the effects of gender and UGT1A1 polymorphisms on the pharmacokinetics of telmisartan. Population pharmacokinetic analyses were performed using data collected prospectively from 58 Chinese patients with mild to moderate essential hypertension (aged 45–72 years; 36 men, 22 women) receiving 80 mg/day telmisartan orally for 4 weeks. Blood samples were collected in heparinized tubes at 0, 0.5, 1, and 6 h on day 28 after telmisartan administration. The plasma concentrations and UGT1A1 genetic variants were determined by high-performance liquid chromatography–mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, respectively. A two-compartment pharmacokinetic structural model with first-order elimination and absorption best described the pharmacokinetic characteristics of telmisartan. Gender and triglyceride influenced the apparent oral clearance (CL) of telmisartan. UGT1A1 (rs4124874) affected the bioavailability (F1) of telmisartan. Lower CL and bioavailability resulted in higher plasma concentrations being observed in female subjects with UGT1A1 CC or CA genotype and high triglyceride. A PopPK model of telmisartan was established to confirm that UGT1A1 genotype, gender and triglyceride can affect the pharmacokinetics of telmisartan in Chinese patients with hypertension. Our findings can provide relevant pharmacokinetic parameters for further study of telmisartan.

Neutrophils activated during acute lung injury (ALI) form neutrophil extracellular traps (NETs) to capture pathogens. However, excessive NETs can cause severe inflammatory reactions. Macrophages are classified as M1 macrophages with proinflammatory effects or M2 macrophages with anti-inflammatory effects. During ALI, alveolar macrophages (AMs) polarize to the M1 phenotype. This study tested the hypothesis that NETs may aggravate ALI or acute respiratory distress syndrome (ARDS) inflammation by promoting alveolar macrophage polarization to the M1 type. Our research was carried out in three aspects: clinical research, animal experiments and in vitro experiments. We determined that NET levels in ARDS patients were positively correlated with M1-like macrophage polarization. NET formation was detected in murine ALI tissue and associated with increased M1 markers and decreased M2 markers in BALF and lung tissue. Treatment with NET inhibitors significantly inhibitor NETs generation, downregulated M1 markers and upregulated M2 markers. Regardless of LPS pre-stimulation, significant secretion of proinflammatory cytokines and upregulated M1 markers were detected from bone marrow-derived macrophages (M0 and M2) cocultured with high concentrations of NETs; conversely, M2 markers were downregulated. In conclusion, NETs promote ARDS inflammation during the acute phase by promoting macrophage polarization to the M1 phenotype. We propose that NETs play an important role in the interaction between neutrophils and macrophages during the early acute phase of ALI.

Lung adenocarcinoma, which is the most common non-small cell lung cancer, is the leading cause of death from cancer worldwide. Epithelial cell transforming sequence 2 (ECT2) is frequently upregulated and acts as an oncogene in various human cancers. In addition, ECT2 was reported to be upregulated in early stage lung adenocarcinoma. However, the detailed role of ECT2 in mediating the malignant phenotypes of lung adenocarcinoma cells has not previously been elucidated. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to examine ECT2 mRNA and protein expression levels, respectively. MTT, wound healing and Transwell assays were conducted to determine cell proliferation, migration and invasion abilities, respectively. In the present study, ECT2 was significantly upregulated in lung adenocarcinoma cell lines (H650, EKVX, HCC4006, HCC827, HCC2935, Hop62 and A549), as compared with a normal lung epithelial cell line (BEAS-2B). Moreover, knockdown of ECT2, induced by transfection with ECT2 siRNA, significantly inhibited the proliferation of lung adenocarcinoma A549 cells, whereas overexpression of ECT2 enhanced A549 cell proliferation. Furthermore, knockdown of ECT2 expression suppressed the migration and invasion of A549 cells, whereas overexpression of ECT2 enhanced the migration and invasion abilities of A549 cells. Notably, inhibition of ECT2 also suppressed the expression levels of N-cadherin and vimentin, whereas it enhanced the expression level of E-cadherin, indicating that ECT2 is associated with the epithelial-mesenchymal transition in A549 cells. On the contrary, overexpression of ECT2 enhanced the expression levels of N-cadherin and vimentin, whereas it reduced the expression level of E-cadherin in A549 cells. In conclusion, the results of the present study suggest that ECT2 has an oncogenic role in lung adenocarcinoma cells. Therefore, ECT2 may be a potential novel target for the treatment of lung adenocarcinoma.

The aim of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios and ratio of geometric means (GMR) of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t and AUC0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94) were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70) and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64) were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for Cmax). The RSABE approach was successful in evaluating the bioequivalence of these two formulations., Graphical abstract Reference-scaled average bioequivalence method was used to evaluate the bioequivalence of two formulations of agomelatine 25-mg tablet with the parent agomelatine for the first time in Chinese population. Standard criteria established by the FDA were used to evaluate the bioequivalence of two formulations of agomelatine 25-mg tablet with metabolites 3-hydroxy-agomelatine and 7-desmethyl-agomelatine.

Aim: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6*10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients. Methods: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M1 (P-88) and M2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites. Results: Patients with the CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M1, and lower concentrations of M2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M1 (K23) and M2 (K24). The K23 value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K24 value of the patients with C/T and T/T genotypes was 0.693- and 0.492-fold, respectively, as low as that of the patients with C/C genotype. Conclusion: CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.

Background: Pyroptosis is the term for caspase-1-dependent cell death associated with pro-inflammatory cytokines. The role of alveolar macrophage (AM) pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains unclear. Methods: C57BL/6 wild-type mice were assigned to sham, lipopolysaccharide (LPS) + vehicle, LPS + acetyl-tyrosyl-valyl- alanyl-aspartyl-chloromethylketone (Ac-YVAD-CMK) and LPS + Z-Asp-Glu-Val-Asp-fluoromethylketone groups. Mice were given intraperitoneal (IP) injections of LPS. Drugs were IP injected 1 h before LPS administration. Mice were sacrificed 16 h after LPS administration, and AMs were isolated. Western blot analysis for active caspase-1 and cleaved caspase-3, evaluation of lung injury and a cytokine release analysis were performed. AMs were treated with LPS and adenosine triphosphate (ATP); caspase-1-dependent cell death was evaluated using flow cytometry; the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) pyroptosomes were examined by immunofluorescence. Results: The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group. In the ex vivo study, the caspase-1/propidium iodide-positive cells, caspase-1 specks and ASC pyroptosomes were up-regulated in AMs following LPS/ATP stimulation. The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death. Ac-YVAD-CMK also reduced the lung injury, pulmonary edema and total protein in bronchoalveolar lavage fluid (BALF). In addition, Ac-YVAD-CMK significantly inhibited interleukin-α 2 (IL-1α 2 ) release both in serum and BALF and reduced the levels of IL-18, tumor necrosis factor-α± (TNF-α±), High Mobility Group Box 1 (HMGB1) in BALF during LPS-induced ALI/ARDS. Conclusions: This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury. These preliminary findings may form the basis for further studies to evaluate this pathway as a target for prevention or reduction of ALI/ARDS.

To eliminate indoor formaldehyde (HCHO) pollution, Pd/CeO2 catalysts with different morphologies of ceria support were employed. The palladium nanoparticles loaded on {100}-faceted CeO2 nanocubes exhibited much higher activity than those loaded on {111}-faceted ceria nanooctahedrons and nanorods (enclosed by {100} and {111} facets). The HCHO could be fully converted into CO2 over the Pd/CeO2 nanocubes at a GHSV of 10 000 h–1 and a HCHO inlet concentration of 600 ppm at ambient temperature. The prepared catalysts were characterized by a series of techniques. The HRTEM, ICP-MS and XRD results confirmed the exposed facets of the ceria and the sizes (1–2 nm) of the palladium nanoparticles with loading amounts close to 1%. According to the Pd 3d XPS and H2-TPR results, the status of the Pd-species was dependent on the morphologies of the supports. The {100} facets of ceria could maintain the metallic Pd species rather than the {111} facets, which promoted HCHO catalytic combustion. The Raman and O 1s XPS resul...

Well-defined {100}-faceted ceria nanocube-supported gold nanoclusters with various morphologies, including individual atom, monolayer, multilayer and nanoparticle, have been synthesized and systematically investigated combined with density functional theory calculations. A strong morphological effect of gold clusters on the reactivity of ceria surface oxygen has been identified. The reducibility and CO oxidation activities of Au/CeO2 catalysts increased significantly as the morphology of the gold clusters changed from single atoms to monolayer, then to multilayer, then nanoparticles. It was revealed that up to a bilayer of gold clusters were needed for desirable catalytic performance in the Au/CeO2 system. The transfer of electrons from gold clusters to the surface Ce–O groups of ceria and strong Au–Au interactions play significant roles in determining the reducibility of surface oxygen of CeO2.

Two types of monolith high-porosity supermacroporous polystyrene materials had been controlled synthesized from water-in-oil Pickering emulsions. The first type, closed-cell high-porosity (up to 91%) supermacroporous (ca. 500 μm) polystyrene materials (CPPs) was prepared by employing amphiphilic carbonaceous microspheres (CMs) as high internal phase emulsion stabilizer without any inorganic salts or further modifying the wettability of the particles. The second type, hierarchical porous polystyrene materials with highly interconnected macropores (IPPs), was constructed from emulsions stabilized simultaneously by CM particles and a little amount of surfactants. Both types of these monolith porous polystyrene materials possessed excellent mechanical strength. The CPPs were used as absorbents for oil-water separation and high absorption capacity, and absorption rate for oils were realized, which was attributed to their porosity structure and the swelling property of the polystyrene, while the IPPs were highly permeable for gases due to their interconnected macropores.

The aim of the present study was to explore the effects of common genetic polymorphisms of cytochrome P450 (CYP)3A4, CYP3A5, cytochrome P450 oxidoreductase (POR) and multidrug resistance protein 1 (MDR1) on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients. The mild-to-moderate essential hypertension patients were recruited to complete the genotyping of CYP3A4, CYP3A5, POR and MDR1 by sequencing. After a 1-week placebo washout period, the subjects received 5 mg oral amlodipine daily for 4 weeks. Serial blood samples were collected prior to the last dosing, and 2, 6 and 24 h post-dosing. Blood pressures were measured prior and subsequent to dosing, and the demographical data were also collected. The blood samples were collected for laboratory testing. The plasma concentrations of amlodipine were determined by high-performance liquid chromatography/tandem mass spectrometry. A total of 60 patients, including 31 males and 29 females, completed the 4-week treatment. The plasma concentration of amlodipine in females at each time point was significantly higher compared to males (P0.05). The genetic polymorphisms of CYP3A4*1G, CYP3A5*3 and POR A503V showed no impact on plasma concentration and efficacy of amlodipine (P>0.05). Gender and MDR1 gene polymorphism may affect the plasma concentration of amlodipine in hypertensive patients. However, there was no impact on the efficacy of amlodipine.

Dimemorfan phosphate has been widely used for 40 years throughout the world for the treatment of coughs. This is the first report on the use of an LC-MS/MS-based assay for the determination of dimemorfan in human plasma using estazolam as an internal standard after one-step protein precipitation with acetonitrile. Chromatographic separation was achieved on a Phenomenex Luna C18 column (3 µm, 50 × 2.0 mm) using a fast gradient method, which involves water and methanol as the mobile phase (both containing 0.1% formic acid). Dimemorfan and estazolam were detected with proton adducts at m/z values of 255.8 155.1 and 295.0 267.0, respectively, in the selected reaction monitoring positive mode. The linear dynamic range of the assay was 0.04–5.00 ng/mL. The chromatographic run time for each plasma sample was

Nerve growth factor (NGF) and dendritic cells (DCs) have been hypothesized to modulate T cell responses in a mouse model of asthma. However, whether NGF plays a role in regulating the maturation and polarization of lung DCs remains unclear. In the present study, the effect of NGF inhibition on the maturation and phenotype of lung DCs was investigated in a mouse model of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and subsequently received anti-NGF treatment. At 24 h following the last challenge, airway responsiveness and inflammation were examined. The concentrations of NGF, interferon (IFN)-γ and interleukin (IL)-4 were analyzed. In addition, maturation and CD103 expression in the lung DCs were investigated. Anti-NGF treatment was found to significantly reduce airway hyperreactivity and inflammation in asthmatic mice. In addition, a subdued T helper 2 (Th2) response was observed, characterized by the downregulation of IL-4 and the upregulation of IFN-γ. Furthermore, the expression of the DC surface molecules, CD80, CD86 and major histocompatibility complex class II, as well as the proportion of lung CD103+ DCs, decreased in the OVA-sensitized and challenged mice. The proportion of lung CD103+ DCs also exhibited a positive correlation with the levels of plasma NGF in the mice. These results may provide an explanation for the role of NGF in amplifying the Th2 response in allergic diseases. Therefore, NGF may promote the maturation and polarization towards a Th2-stimulating phenotype of activated DCs, contributing to an amplification of the Th2 response in asthma.

A series of amphiphilic carbonaceous microspheres-supported Pd catalysts have been prepared and their performances for the hydrodeoxygenation of vanillin have been investigated in both a pure aqueous phase and in water–oil biphasic systems. The wettability of the catalyst could be facilely tuned by adjusting the hydrothermal treatment temperature during the synthesis of the carbonaceous microspheres or by a post-treatment process in alkaline solution. In the aqueous phase reactions, the more hydrophilic the catalyst, the more active it was for the hydrodeoxygenation of vanillin. And the wettability of the support affects the activity through the interaction between the catalysts and substrates/products. In the case of a water–oil biphase, the wettability of the support played a key role in forming Pickering emulsions. It was found that the selectivity of the hydrodeoxygenation reactions was determined by the type of Pickering emulsion and high selectivity of p-creosol could be achieved in the water-in-oil emulsion systems.

Reducing the cost of PEM water electrolyser is still a big challenge for renewable energy storage. Though there are some reports which have achieved very low Ir loading (0.1~0.2mg/cm2) in membrane electrode assemblies (MEA) for PEM water electrolyser, the other issues such as the performance and stability of MEA, the reduction of Pt loading in cathode and the scalability of preparation method of MEA still need further investigation for developing low cost and high performance PEM water electrolyser. In this work, to develop high performance anode with low Ir loading, highly active Iridium oxohydroxides were supported on conductive titanium metal nanosphere as the anode catalyst. The diatmeter of metal Ti nanosphere ranges from 60-200nm, and the Iridium oxohydroxides loaded on Ti support shows a particle size between 1.5-3nm. The OER activity of the catalyst with various Ir loading was characterized, and the catalyst with 10% Ir loading exhibited highest Ir mass activity (1700A/g @η=0.37V), it is about 6 times as the commercial IrO2. Increasing the loading of Ir will lead to the decline of Ir mass activity, this may be due to the limited surface area of Ti nanosphere. The stability of the catalyst (Ir loading 10%) was characterized by CV scans between 0.4-1.5V (vs.RHE) in 0.5M H2SO4. After 2000 cycles, the active sites of IrOx declined only 18%, and the catalyst does not show an obviously rising in resistance from EIS characterization, indicating a good stability both on active sites and support. The MEAs using such IrOx/Ti as the anode were prepared by conventional CCM method, and the Pt loading (20% wt. Pt/C) in cathode was reduced to about 0.2mg/cm2. The anode with various Ir loading and membrane with different thickness were determined at atmosphere under 80 degrees. The electrolyser with Ir loading 0.13mg/cm2 in anode, Pt loading 0.18mg/cm2 in cathode and N212 membrane achieved 1.623V at 1A/cm2 and 1.778V at 2A/cm2, which exhibits a good performance with such low noble metal loading. Further decreasing the Ir loading in anode catalyst layer will lead to performance degradation, but the rising of voltage was only 50-60mv at 1A/cm2 when Ir was reduced to 0.08 mg/cm2. With respect of the durability of MEAs, an electrolyser using Nafion 117 as the membrane, and 0.08 mg /cm2 Ir in MEA was tested under 1A/cm2. After 850h, the voltage increased from 1.79V to 1.83V, and the degradation rate is below 50μV/h, this suggests a good stability of supported Iridium oxohydroxides, and the stability of electrolyser with N212 membrane is now ongoing. Figure 1

One-dimensional structure with high surface area, oriented charge transfer and facile mass transfer is a promising solution to reduce the loading amount of noble metal as catalyst in PEM water electrolysis. In this work, TiO2 nanotube array (TNTA) is applied to decorate IrO2 to construct highly ordered 1-D electrode. Firstly, TNTA, synthesized by anodizing in hydrofluoric solution, is used as substrate as its great stability in both acidic and oxidizing environment. By considering the insufficient conductivity of TiO2, modification, including calcining in hydrogen or cathodic polarization, is conducted to improve its conductivity. Both the method can reduce part of Ti4+ to Ti3+ to achieve improving conductivity. By comparison, cathodic polarization treated TNTA performs higher carrier density without hydrogen brittleness. Iridium oxide is electro-deposited onto TNTA. By increasing the conductivity of TNTA, IrO2/reduced-TNTA shows a three order of magnitude higher OER activity than IrO2/pristine-TNTA. Reduced-TNTA is predictably unstable in oxidizing environment. By increasing the coverage of IrO2, the stability of IrO2/reduced-TNTA increase as the surface layer of IrO2 will isolate the unstable reduced-TNTA from oxidizing species generated during OER to prevent decrease of substrate conductivity. Secondly, as a compact layer of IrO2 on the surface of reduced-TNTA is essential to its stability, TNTA is used as sacrificed template to fabricate one-dimensional IrO2 nano-array electrode. By removing TNTA, the mass-ratio surface area of IrO2 is double. Hot-press treatment followed by two-step etching of TNTA is conducted to transfer the IrO2 nano-array to Nafion membrane. With 1500 nanometer long TNTA prepared in hydrofluoric sodium solution is used as template, iridium oxide nanotube arrays and hollow nanowire arrays is achieved by applying different scan rate in deposition. The nanotube array is consisted with intact nanotube and porous nanotube surrounding it, which is corresponding to the structure of template. A mechanism of the scan rate controlling deposition is proposed. The deposition of iridium oxide on TNTA can be divided into the deposition near the mouth and the deposition along the tube wall. With continuously depositing, the concentration in the nanotube will gradually decrease and form a gradient. While the concentration near the mouth keep constant as its sufficient diffusion of precursor from the bulk electrolyte. So, if the duration of deposition in a single cycle is long enough, iridium will be preferentially deposited at the mouth of TNTA. And once the cover layer on the top surface is formed, the diffusion into the tube will be limited and further deposition will only lead to the thickening of the cover layer. As a result, with slow scan rate, the cover layer will shell the mouth of TNTA before the constant layer of iridium is deposited throughout the template, and results in nanotube arrays. And with fast scan rate, the deposition is more even, and the hollow nanowire arrays is obtained. Electrochemical study shows that the current density of iridium oxide nano-arrays in OER is positive correlated to its surface area, and it shows better performance of mass-ratio activity than commercial iridium oxide nanoparticle as anode in MEA.

A novel simple bioanalytical method of high performance liquid chromatography (HPLC) for simultaneous quantification of morinidazole and its carbonylation metabolite (M1) in human plasma was developed and validated. The calibration curves for morinidazole and M1 were linear over concentration ranges of 23.99-1.464×10(4)μgL(-1) and 5.407-3300μgL(-1), respectively. Intra- and inter-day precision and accuracy results satisfied the acceptable criteria for bioanalytical method validation. This method could be a useful method for clinical pharmacokinetic studies of morinidazole and its carbonylation metabolite, and it has been applied to a pharmacokinetic study involving 11 renal insufficiency patients and 11 healthy volunteers.

1. The immunosuppressant tacrolimus (TAC) is a substrate of cytochrome P450 3A2 (CYP3A2) and P-glycoprotein (P-gp) in rats. Amlodipine (AML) is an inhibitor of CYP3A2 in rats. We investigated the effect of AML on the pharmacokinetics of TAC in rats. 2. When co-administered with TAC orally or intravenously, AML decreased the oral clearance and raised the blood concentration of TAC in rats, but the T1/2 of TAC was not significantly affected by AML. Upon oral administration of TAC, the effect of 15 mg/kg of AML on the AUC of TAC was lower than that seen with 5 or 10 mg/kg. However, upon intravenous TAC administration, the effect of 15 mg/kg of AML on the AUC of TAC was higher than that seen with 5 mg/kg. 3. AML is an inhibitor of P-gp and CYP3A2 in rats. If AML and TAC are co-administered orally, AML elicits greater inhibition in P-gp than CYP3A2 during first-pass metabolism. If AML is given orally and TAC given intravenously concurrently, AML mainly inhibits CYP3A2 activity and increases the blood concentration of TAC. There are significant pharmacokinetic interactions between TAC and AML. AML raises the blood concentration of TAC in rats probably by inhibiting P-gp and CYP3A2.

The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC₀-∞ of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.

Tolvaptan is a selective vasopressin V(2)-receptor antagonist mainly used for the treatment of hyponatremia. This study described the development and validation of an LC-MS/MS method for the determination of tolvaptan in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 2-demethyl tolvaptan (internal standard, IS). Chromatographic separation was performed on a Zorbax XDB C(18) column with an isocratic mobile phase consisting of water (containing 0.1% formic acid) and methanol (25:75, v/v). Determination of the analytes was achieved by tandem-mass spectrometry with positive electrospray ionization. The multiple reaction monitoring (MRM) transitions were performed at m/z 449.2→252.1 for tolvaptan and m/z 435.2→238.1 for IS. The assay was linear over the concentration range of 0.457-1000ng/mL, with a lower limit of quantification of 0.457ng/mL. The intra- and inter-day precisions at three concentration levels (0.914, 111 and 800ng/mL) were less than 15% and their accuracies were within the range of 97.7-107.8%. The mean recovery ranged from 99.2 to 104.6% and the matrix effect from 89.3 to 99.5%. Tolvaptan was stable under all tested conditions. This validated method was successfully applied to a pharmacokinetic study in healthy volunteers after oral administration of single-dose tolvaptan tablets.