Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial.

Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration-time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

PCSK9 inhibitor recaticimab for hypercholesterolemia on stable statin dose: a randomized, double-blind, placebo-controlled phase 1b/2 study.

BACKGROUND: Recaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia. METHODS: In this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule). RESULTS: A total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from -48.37 to -59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase. CONCLUSION: Recaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT03944109.

Oxygen Self-Supply Engineering-Ferritin for the Relief of Hypoxia in Tumors and the Enhancement of Photodynamic Therapy Efficacy.

Hypoxia is a hallmark of the tumor microenvironment (TME) that promotes tumor development and metastasis. Photodynamic therapy (PDT) is a promising strategy in the treatment of tumors, but it is limited by the lack of oxygen in TME. In this work, an O2 self-supply PDT system is constructed by co-encapsulation of chlorin e6 (Ce6) and a MnO2 core in an engineered ferritin (Ftn), generating a nanozyme promoted PDT nanoformula (Ce6/Ftn@MnO2 ) for tumor therapy. Ce6/Ftn@MnO2 exhibits a uniform small size (15.5 nm) and high stability due to the inherent structure of Ftn. The fluorescence imaging and immunofluorescence analysis demonstrate the pronounced accumulation of Ce6/Ftn@MnO2 in the tumors of mice, and the treatment significantly decreases the expression of hypoxia-inducible factor (HIF)-1α. The Ce6/Ftn@MnO2 nanoplatform exerts a more potent anti-tumor efficacy with negligible damage to normal tissues compared to the treatment with free Ce6. Moreover, the weak acidity and the presence of H2 O2 in TME significantly enhances the r1 relativity of Ce6/Ftn@MnO2 , resulting in a prominent enhancement of MRI imaging in the tumor. This bio-mimic Ftn strategy not only improves the in vivo distribution and retention of Ce6, but also enhances the effectiveness and precision of PDT by TME modulation.

Nitric-Oxide-Releasing aza-BODIPY: A New Near-Infrared J-Aggregate with Multiple Antibacterial Modalities.

The development of near-infrared (NIR) J-aggregates has received increasing attention due to their broad applications. Here, we report the nitrosation of an amine-containing aza-BODIPY precursor (BDP-NH2 ), affording the first nitric oxide (NO)-releasing NIR J-aggregate (BDP-NO). The introduction of N-nitrosamine moieties efficiently inhibits the aromatic interactions of BDP-NH2 , which instead promotes the formation of J-aggregates within micellar nanoparticles with a remarkable bathochromic shift of ≈109 nm to the NIR window (820 nm). Interestingly, the NO release and photothermal conversion efficiency (PTCE) can be delicately tuned by the loading contents of BDP-NO within micellar nanoparticles, thereby enabling multiple antibacterial modalities by exploring either NO release, photothermal therapy (PTT), or both. We demonstrate the combination of NO and PTT can elevate antibacterial activity while attenuating PTT-associated inflammation for the in vivo treatment of MRSA infection.

Fluorinated Copolypeptide-Stabilized Microbubbles with Maleimide-Decorated Surfaces as Long-Term Ultrasound Contrast Agents.

Gas-filled microbubbles (MBs) have been clinically used as ultrasound (US) contrast agents for disease diagnosis and treatment. However, it remains a great challenge to resolve the dilemma of stability and contrast enhancement of MBs. Herein, amphiphilic copolypeptides bearing fluorinated blocks are synthesized to stabilize perfluorocarbon (PFC)-filled MBs, exhibiting unique stability under both long-term storage and US imaging conditions. The fluorinated inner layer reduces the internal Laplace pressure and greatly improves the stability of MBs, which can be further reinforced by crosslinking of the dipropargyl-containing middle blocks. To overcome the suppressed nonlinear oscillation of polymer shells, maleimide groups are introduced onto the surface of MBs, enabling in situ reaction with plasma proteins to enhance second harmonic signals without compromising the stability of MBs, conferring better US imaging performance than that of SonoVueTM MBs.

Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report.

An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in Wuhan, China, with cases now confirmed in multiple countries. The clinical course of patients remains to be fully characterized, clinical presentation ranges from asymptomatic infection to acute respiratory distress syndrome and acute renal failure, and no pharmacological therapies of proven efficacy yet exist. We report a case of SARS-CoV-2 infection in a renal transplant recipient with excellent outcome. This case states the importance of close monitoring of the concentration of cyclosporine in patients treated with lopinavir/ritonavir; the routine treatment of corticosteroid can be continued. This is a rare report of SARS-CoV-2 infection in a renal transplant recipient. Further data are needed to achieve better understanding of the impact of immunosuppressive therapy on the clinical presentation, severity, and outcome of SARS-CoV-2 infections in solid organ transplant recipients.

Preparation and evaluation of phytantriol liquid crystal as a liquid embolic agent.

Transcatheter arterial chemoembolization (TACE) is the preferred treatment for patients with advanced hepatocellular carcinoma (HCC), but it lacks safe and effective embolic agents. 5-Fluorouracil (5-FU) is a broad-spectrum anticancer drug, but its clinical application is limited due to drug resistance and toxic side effects. Therefore, in this study, we developed a new liquid embolic agent with 5-FU as the model drug. We found that this liquid embolic agent possesses good gelling properties and embolic effects. An in vitro drug release model of the agent conformed to the Weibull model. Cumulative release of the drug over 7 d was ∼90%, consisting of an initial burst followed by sustained release. Cytotoxicity testing showed that each liquid embolic composition is cytocompatible and only mildly cytotoxic. Pharmacokinetic experiments showed that the formulation significantly prolongs the t1/2 of 5-FU (approximately five times that of 5-FU solution) and 5-FU residence time in the body (approximately three times that of 5-FU solution). These results indicate that the liquid embolic agent has embolic capacity and could be used as a potential therapeutic method for TACE.

Influencing factors of physicians' prescription behavior in selecting essential medicines: a cross-sectional survey in Chinese county hospitals.

BACKGROUND: To explore the key factors affecting prescription practices of essential medicines in Chinese county hospital. National essential medicine policy (NEMP) plays important roles in health care system, especially in developing countries. As a fundamental component in the Chinese health system reform, NEMP was implemented in primary health care institutions during the first stage of reform. As it is rolled out, priority usage and zero-mark-up policy of essential medicines are to be applied in every government-run healthcare institution. However, the intention and influence factors of physicians on priority selecting essential medicine remains unclear. METHODS: Based on the theory of planned behavior, a cross-sectional questionnaire survey was conducted to analyze physicians' intention, attitude, subjective norms (SNs) and perceived behavioral control (PBC) on prescrictions and their actual behavior on selection of essential medicines. RESULTS: Two hundred eighty-two physicians participated in the structural questionnaire interview. The final structural equation model reflected influencing factors affecting physicians' prescribing behavior (χ2/df = 1.32, GFI = 0.99, IFI = 0.99). Structural equation model analysis showed that attitude, other influencers and institutional environment, and PBC significantly affected behavioral intention. However, the control extent of cognition behavior of physicians prescribing had no significant positive effect on the priority usage of essential medicines. CONCLUSION: Investigation results demonstrate physicians are unaware of NEMP design and implementation plans. To help enhance rational use of essential medicines we suggest educating physicians on the value of NEMP, and integrating the drug shortage report into the essential medicine (EM) bidding system seamless communication with pharmaceutical manufacturers' credit information system.

The short-term effects of air pollutants on hospitalizations for respiratory disease in Hefei, China.

Previous studies have shown that ambient air pollution is associated with respiratory morbidity. However, the effects of air pollutants on health have rarely been studied in China. Our study aimed to estimate the short-term effects of particulate air pollutants on hospitalizations for three types of respiratory disease: pneumonia, chronic obstructive pulmonary disease (COPD), and asthma. We collected data on daily admissions for patients with each disease from the New Rural Cooperative Medical System (NRCMS) in Hefei, China. Daily records of air pollutants and meteorological data from January 2014 to March 2016 were also obtained. Distributed lag nonlinear models were employed in the analysis to evaluate the association between daily air pollutants and admissions. The highest effect of each pollutant on COPD hospital admission was observed with PM2.5 at lag 12 (RR = 1.068, 95% CI 1.017 to 1.121) and PM10 at lag 10 (RR = 1.031, 95% CI 1.002 to 1.060), for an increase of 10 µg/m3 in concentrations of the pollutants. The short-term effects of PM10 on asthma hospital admissions peaked at lag 12 (RR = 1.057, 95% CI 1.010 to 1.107). According to our stratified analysis, we found that the effects on COPD admission were more pronounced in the warm season than in the cold season, and the elderly (≥ 65 years) and females were more vulnerable to air pollution.

Trends analysis for drug utilization in county public hospitals: a sample study of the pilot area of health care reform in China.

BACKGROUND: Changes in the national drug policy always have impact on the drug utilization. In the context of China health care reform, what changes had happened in the trend of drug utilization in public hospitals? Has this change met the expectations of policy design? This study was conducted to explore the trend of medicine consumption in county public hospitals before and after health care reform, and to provide real-world evidence to help assess the effectiveness of national drug policy. METHODS: A cross-sectional study was performed to investigate the drug utilization trends of 6 county public hospitals in Anhui Province, which is the first pilot area of China health care reform. Data were collected before and after the implementation of the China National Essential Medicine Policy (NEMP) to analyse the drug utilization indicators, such as the drug utilization constituent ratio, the rate of essential medicine usage and the rate of antibiotic consumption. RESULTS: Chemicals are used most frequently and account for 60%~ 70%, followed by oral agents of proprietary Chinese medicine. The results also show increased consumption of Chinese medicine injections (χ2 = 28.428, P < 0.01). The top 3 chemical medicines consumed were anti-infective drugs (12.92%), cardiovascular system drugs (11.61%), and digestive system drugs (8.42%). For Chinese traditional medicine, the top 3 drugs consumed were internal medicine drugs (66.03%), surgical drugs (8.45%), and gynaecological drugs (7.70%). The total sales amounts of drugs covered by medical insurance are at a high level (all above 80%), whereas essential medicines are less than 50% at almost all county-level medical institutions. CONCLUSIONS: This study uncovered the changing tendency of medicine usage under the implementation of the reform. Chinese medicine injections and anti-infective drugs have always been a sustained concern of pharmacovigilance. It is noteworthy that although essential medicines are advocated for as a priority for use in the government-run hospital, the consumption proportion of these medicines is lower than expected.

Association between circulating leptin levels and multiple sclerosis: a systematic review and meta-analysis.

AIM: Leptin, synthesised by adipocytes, has been identified as a hormone that can influence inflammatory activity. Several studies have investigated leptin levels in patients with multiple sclerosis (MS), but the results are not consistent. This study aims to derive a more precise evaluation on the relationship between circulating leptin levels and MS. DESIGN: A comprehensive literature searched up to July 2017 was conducted to evaluate the association of circulating leptin levels and MS. The random-effect model was applied to calculate pooled standardised mean difference (SMD) and its 95% CI. MAIN OUTCOME MEASURES: Circulating leptin levels of patients with MS and healthy controls. RESULTS: Of 2155 studies identified, 33 met eligibility criteria and 9 studies with 645 patients with MS and 586 controls were finally included in the meta-analysis. Meta-analysis revealed that, compared with the healthy control group, the MS group had significantly higher plasma/serum leptin levels, with the SMD of 0.70% and 95% CI (0.24 to 1.15). Subgroup analyses suggested that the leptin levels of patients with MS were associated with region, age, study sample size, measurement type, gender and blood sample type. CONCLUSION: Overall, our study suggests that patients with MS have a significantly higher leptin level than in healthy controls. Further mechanism studies and longitudinal large cohort studies are still needed to further reveal the role of leptin in the pathogenesis of MS.

Development of a quality instrument for assessing the spontaneous reports of ADR/ADE using Delphi method in China.

BACKGROUND AND AIM: The frequently low quality of submitted spontaneous reports is of an increasing concern; to our knowledge, no validated instrument exists for assessing case reports' quality comprehensively enough. This work was conducted to develop such a quality instrument for assessing the spontaneous reports of adverse drug reaction (ADR)/adverse drug event (ADE) in China. METHODS: Initial evaluation indicators were generated using systematic and literature data analysis. Final indicators and their weights were identified using Delphi method. The final quality instrument was developed by adopting the synthetic scoring method. RESULTS: A consensus was reached after four rounds of Delphi survey. The developed quality instrument consisted of 6 first-rank indicators, 18 second-rank indicators, and 115 third-rank indicators, and each rank indicator has been weighted. It evaluates the quality of spontaneous reports of ADR/ADE comprehensively and quantitatively on six parameters: authenticity, duplication, regulatory, completeness, vigilance level, and reporting time frame. CONCLUSION: The developed instrument was tested with good reliability and validity, which can be used to comprehensively and quantitatively assess the submitted spontaneous reports of ADR/ADE in China.

[Research on the Application of Lean Management in Medical Consumables Material Logistics Management].

Objective: Solve the problems of high cost, low utilization rate of resources, low medical care quality problem in medical consumables material logistics management for scientific of medical consumables management. Methods: Analysis of the problems existing in the domestic medical consumables material logistics management in hospital, based on lean management method, SPD(Supply, Processing, Distribution) for specific applications, combined HBOS(Hospital Business Operation System), HIS (Hospital Information System) system for medical consumables material management. Results: Achieve the lean management in medical consumables material purchase, warehouse construction, push, clinical use and retrospect. Conclusion: Lean management in medical consumables material can effectively control the cost in logistics management, optimize the alocation of resources, liberate unnecessary time of medical staff, improve the quality of medical care. It is a scientific management method.

[Discussion on the Monitoring of Medical Device Adverse Event].

Objective: Analyzing the status of medical device adverse events, the function of the clinical medical engineers in medical device adverse event monitoring was investigated. Methods: Through introducing the functions of the various departments in the medical device adverse event monitoring, the technical requirements and management responsibilities of clinical medical engineer and medical staff were defined. Results: Enhancing the function of clinical medical engineers in medical device adverse event monitoring,which is an effective measure to prevent medical device adverse events. Conclusion: Play the functions of clinical engineers in the medical device adverse event monitoring, which is significant to improve the using quality of medical devices and to ensure patient safety.

Total flavonoids of Bidens bipinnata L. ameliorate experimental adjuvant-induced arthritis through induction of synovial apoptosis.

BACKGROUND: Bidens bipinnata are widely distributed in China, which have been widely used as a traditional Chinese medicine. The aim of this study was to examine the effect of total flavonoids of Bidens pilosa L. (TFB) on adjuvant arthritis (AA) and its possible mechanisms. METHODS: The macroscopic scoring of paw edema, secondary paw swelling, and polyarthritis index were measured. Histological examination of the joints and the serum concentrations of IL-6, IL-1beta, and TNF-alpha were examined. Apoptosis in synovial tissue was detected. The expression of Caspase 3 cleavage, serves as a marker undergoing apoptosis, was confirmed by Western blot. RESULTS: TFB attenuated the severity of arthritis on paw edema, hind paw volume, and polyarthritis index of AA rats, improved the histological status in AA rats as well. TFB can inhibit the production of IL-6, IL-1beta, and TNF-alpha from serum. Clear DNA ladder formation was observed in DNA extraction of synovium from TFB treated AA rats. The number of apoptosis was increased with TFB treatment in TUNEL assay. TFB treatment on AA rats significantly increased the expression of Caspase 3 in synovium. CONCLUSIONS: Our data suggest that TFB has a significant anti-arthritic effect in AA through the induction of apoptosis in synovial.

An adhesion-switchable hydrogel dressing for painless dressing removal without secondary damage.

Hydrogels with strong adhesion to wet tissues are considered promising for wound dressings. However, the clinical application of adhesive hydrogel dressing remains a challenge due to the issues of secondary damage during dressing changes. Herein, we fabricated an adhesion-switchable hydrogel formed with poly(acrylamide)-co-poly(N-isopropyl acrylamide), quaternary ammonium chitosan and tannic acid. This hydrogel forms instant and robust adhesion to the skin at body temperature. However, as the temperature rises above the lower critical solution temperature (LCST), the hydrogel loses its adhesion towards the wound area due to the temperature-dependent volume phase transition of the copolymer, occurring around 45 °C. Consequently, the designed hydrogel can be easily detached from adhered tissues upon demand, providing a facile and effective method for painless dressing changes without secondary damage. This hydrogel holds great promise for long-term application in wound dressings.

Cost-effectiveness of palbociclib plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer - A Chinese healthcare system perspective.

Aim: To evaluate the cost-effectiveness of palbociclib plus fulvestrant in the second-line treatment of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer based on the latest published follow-up data from the perspective of the Chinese healthcare system. Methods: In view of the PALOMA-3 trial, a Markov model was built for this purpose, which included three health states: progression-free survival (PFS), progressed disease (PD), and death. The cost and health utilities were mainly derived from the published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to verify the robustness of the model. Results: In the base case analysis, compared with the placebo plus fulvestrant arm, the palbociclib plus fulvestrant arm yielded an additional 0.65 quality-adjusted life years (QALYs) (2.56 QALYs vs. 1.90 QALYs) with an incremental cost of $36,139.94 ($55,482.06 vs. $19,342.12), resulting an incremental cost-effectiveness ratio (ICER) of $55,224.90/QALY, which was deeply higher than a willingness-to-pay (WTP) threshold of $34,138.28 per QALY in China. The results of one-way sensitivity analysis indicated that the utility of PFS, cost of palbociclib, and cost of neutropenia had a great influence on the ICER. Conclusions: Palbociclib plus fulvestrant is unlikely to be cost-effective in comparison with placebo plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer.

Protein encapsulation of nanocatalysts: A feasible approach to facilitate catalytic theranostics.

Enzyme-mimicking nanocatalysts, also termed nanozymes, have attracted much attention in recent years. They are considered potential alternatives to natural enzymes due to their multiple catalytic activities and high stability. However, concerns regarding the colloidal stability, catalytic specificity, efficiency and biosafety of nanomaterials in biomedical applications still need to be addressed. Proteins are biodegradable macromolecules that exhibit superior biocompatibility and inherent bioactivities; hence, the protein modification of nanocatalysts is expected to improve their bioavailability to match clinical needs. The diversity of amino acid residues in proteins provides abundant functional groups for the conjugation or encapsulation of nanocatalysts. Moreover, protein encapsulation can not only improve the overall performance of nanocatalysts in biological systems, but also bestow materials with new features, such as targeting and retention in pathological sites. This review aims to report the recent developments and perspectives of protein-encapsulated catalysts in their functional improvements, modification methods and applications in biomedicine.