A first-in-human study of Brozopentyl Sodium, following single and multiple ascending intravenous infusion in Chinese healthy volunteers.

BACKGROUND: Brozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation. PURPOSE: This study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers. METHODS: The study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2-6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted. RESULTS: In the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated. CONCLUSION: BZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.

Population pharmacokinetic analysis and dosing regimen optimization of teicoplanin in critically ill patients with sepsis.

Objectives: Teicoplanin has been extensively used in the treatment for infections caused by gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). However, current teicoplanin treatment is challenging due to relatively low and variable concentrations under standard dosage regimens. This study aimed to investigate the population pharmacokinetics (PPK) characteristics of teicoplanin in adult sepsis patients and provide recommendations for optimal teicoplanin dosing regimens. Methods: A total of 249 serum concentration samples from 59 septic patients were prospectively collected in the intensive care unit (ICU). Teicoplanin concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modeling approach. Monte Carlo simulations were performed to evaluate currently recommended dosing and other dosage regimens. The optimal dosing regimens were defined and compared by different pharmacokinetic/pharmacodynamic parameters, including trough concentration (Cmin), the ratio of 24-h area under the concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC), as well as the probability of target attainment (PTA) and the cumulative fraction of response (CFR) against MRSA. Results: A two-compartment model adequately described the data. The final model parameter estimates for clearance, central compartment volume of distribution, intercompartmental clearance and peripheral compartment volume were 1.03 L/h, 20.1 L, 3.12 L/h and 101 L, respectively. Glomerular filtration rate (GFR) was the only covariate that significantly affected teicoplanin clearance. Model-based simulations revealed that 3 or 5 loading doses of 12/15 mg/kg every 12 h followed by a maintenance dose of 12/15 mg/kg every 24 h-72 h for patients with different renal functions were required to achieve a target Cmin of 15 mg/L and a target AUC0-24/MIC of 610. For MRSA infections, PTAs and CFRs were not satisfactory for simulated regimens. Prolonging the dosing interval may be easier to achieve the target AUC0-24/MIC than reducing the unit dose for renal insufficient patients. Conclusion: A PPK model for teicoplanin in adult septic patients was successfully developed. Model-based simulations revealed that current standard doses may result in undertherapeutic Cmin and AUC, and a single dose of at least 12 mg/kg may be needed. AUC0-24/MIC should be preferred as the PK/PD indicator of teicoplanin, if AUC estimation is unavailable, in addition to routine detection of teicoplanin Cmin on Day 4, follow-up therapeutic drug monitoring at steady-state is recommended.

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF.

Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4-VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4-VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.

Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation.

We aimed to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model from healthy Chinese subjects and real-world non-valvular atrial fibrillation (NVAF) patients. We also investigated meaningful intrinsic and extrinsic factors and related biomarkers for bleeding events. We characterized the integrated PK/PD models based on rich PK/PD data [dabigatran concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and anti-factor IIa (anti-FIIa) activity] from 118 healthy volunteers and sparse PD data [APTT, PT, and anti-FIIa] from 167 patients with NVAF after verifying the model extrapolation performance. We also documented the correlations between PD biomarkers and clinically relevant bleeding events over one year. Next, we used the final integrated PK/PD model (a two-compartment, linear model with first-order absorption) to evaluate the influence of dosage and individual covariates on PD parameters. The age, high-density liptein cholesterol (HDL-C), and creatinine clearance (CrCL) improved the PK model fit. The linear direct-effects PD model described the correlation between APTT, PT, and anti-FIIa and plasma concentration. CrCL improved the PD model fit. Anti-FIIa was more sensitive to the increase in dabigatran exposure than APTT and PT in the PD model. Therefore, fixed dabigatran doses could be prescribed for patients with NVAF without adjusting for age and HDL-C. We observed an elevated bleeding tendency with higher peak and trough values of APTT, PT, and anti-FIIa. Randomized studies should be performed to evaluate the efficacy and safety of low-dose dabigatran in Chinese patients with NVAF.

Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae.

Objective: Cefoperazone/sulbactam is a commonly used antibiotic combination against the extended-spectrum beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new cefoperazone/sulbactam combination (3:1) for Enterobacteriaceae infection via model-informed drug development (MIDD) approaches. Methods: Sulperazon [cefoperazone/sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free drug concentration exceeded the minimum inhibitory concentration (%fT>MIC) was used as the pharmacokinetic/pharmacodynamic indicator correlated with efficacy. Models were developed to characterize the PK profile of cefoperazone and sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of cefoperazone/sulbactam (3:1) for the treatment of infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria. Results: Two 2-compartment models were developed to describe the PK profiles of cefoperazone and sulbactam. Simulation results following the single-dose showed that the regimens of cefoperazone/sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of cefoperazone/sulbactam (4 g, TID, 3 g:1 g) showed slightly better antibacterial effect than cefoperazone/sulbactam (6 g, BID, 4 g:2 g) against the Escherichia coli (ESBL-) and Klebsiella pneumoniae (ESBL-). For the other tested bacteria, the above regimens achieved a similar PTA. Conclusions: Cefoperazone/sulbactam (3:1) showed similar bactericidal activity to sulperazon [cefoperazone/sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and cefoperazone-resistant E. coli and K. pneumoniae, Cefoperazone/sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.

Safety, tolerance, pharmacokinetic and pharmacodynamic properties of thrombopoietin mimetic peptide for injection in Chinese healthy volunteers: a randomized, placebo-controlled, double-blind study.

The thrombopoietin mimetic peptide for injection is a second-generation thrombopoietin receptor agonist (TPO-RA) used in the treatment of patients with immune thrombocytopenia. The aim of the present study was to assess the safety, tolerance, pharmacokinetic and pharmacodynamic properties of thrombopoietin mimetic peptide for injection in Chinese healthy volunteers. A randomized, placebo-controlled, double-blind, dose-escalation study was conducted in healthy Chinese subjects aged 18-50 years. Thirty subjects received single subcutaneous injection of 0.3 µg/kg, 1.0 µg/kg, 2.0 µg/kg thrombopoietin mimetic peptide or placebo. Thrombopoietin mimetic peptide was safe and well tolerated at doses of 0.3-2.0 µg/kg. There was no significant change in mean platelet count (PLT) from baseline at the 0.3 µg/kg or placebo groups. The mean PLT of subjects in the 1.0 µg/kg and 2.0 µg/kg groups peaked at day 12 (± 1), began to decline around day 17, and returned to the baseline level at day 28 (± 1). Platelet aggregation rates of the three dose groups showed no significant change before and after administration. Serum concentrations of thrombopoietin mimetic peptide in all subjects were below the quantization limit. This was the first study to demonstrate that subcutaneous injection of thrombopoietin mimetic peptide at doses of 0.3-2.0 µg/kg was safe and well tolerated in Chinese healthy subjects. As a second-generation TPO-RA, thrombopoietin mimetic peptide is effective at improving PLT after single subcutaneous injection at dose of ≥1 µg/kg.P lain l anguage s ummaryWhat is the context?● Immune thrombocytopenia (ITP) is a rare, serious autoimmune disorder characterized by low platelet count (PLT) without an alternate cause. The treatment goal of ITP is to increase the platelet count to a safe level that can stop active bleeding and reduce the risks of future bleeding.● Thrombopoietin receptor agonists (TPO-RAs, e.g. eltrombopag, avatrombopag, hetrombopag, and romiplostim) have shown high response rates in stimulating platelet production and reducing the risk of bleeding. TPO-RAs provide ITP patients with well-tolerated, long-term treatment choices.What is new?● The thrombopoietin mimetic peptide for injection is a new TPO-RAs developed by Shandong Quangang Pharmaceutical Co., Ltd. (China).● This study showed that thrombopoietin mimetic peptide is effective at improving PLT after a single subcutaneous injection.● The thrombopoietin mimetic peptide is safe and well-tolerated in Chinese healthy subjects.What is the impact?● This study provides evidence for the further development potential of the thrombopoietin mimetic peptide.

Non-vitamin K antagonist oral anticoagulants in venous thromboembolism patients: a meta-analysis of real-world studies.

BACKGROUND: The real-world studies on recurrent venous thromboembolism (VTE) and bleeding events of non-vitamin K antagonist oral anticoagulants (NOACs) in VTE patients have reported conflicting findings. Our study aimed to provide the direct comparison evidence of different NOACs for VTE patients in clinical practice settings. METHODS: Search of the medical literature was conducted using PubMed, Web of Science, EMBASE, Clinical Trials.gov, and the Cochrane Library from inception to March 22, 2021. Among the 19,996 citations retrieved, a total of 63,144 patients from 6 studies were analyzed. Clinical outcomes included recurrent VTE, death, and different bleeding events. RESULTS: Adjusted hazard ratio (HR) analysis suggested that apixaban had significant lower bleeding riskthan rivaroxaban (major, minor and any bleeding: HR = 0.61, 0.56, 0.70; p = 0.008, < 0.0001, 0.006, respectively), but no statistics difference found in recurrent VTE events (HR = 1.02, 95% confidence interval (CI) 0.71-1.47, p = 0.93). There was no significant difference of major bleeding between dabigatran and rivaroxaban (odds ratios (OR) = 0.41, 95% CI 0.09-1.90, p = 0.25), apixaban and dabigatran (OR 0.64, 95% CI 0.15-2.72, p = 0.83). No significant difference was found in the comparison of edoxaban and other NOACs in VTE recurrence, major bleeding and composite outcome. CONCLUSIONS: In the prevention of bleeding events, apixaban was associated with a lower risk than rivaroxaban, but equivalent efficacy for different NOACs in prevention of recurrent VTE. Evidence generated from the meta-analysis based on real-world data can help to guide selection between apixaban and rivaroxaban in routine clinical practice. TRIAL REGISTRATION: This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology statements and was registered with PROSPERO (CRD42019140553).

Thymosin-α1 binds with ACE and downregulates the expression of ACE2 in human respiratory epithelia.

BACKGROUND: Thymosin-α1 has been implicated into the treatment of novel respiratory virus Coronavirus Disease 2019 (COVID-19), but the underlying mechanisms are still disputable. AIM: Herein we aimed to reveal a previously unrecognized mechanism that thymosin-α1 prevents COVID-19 by binding with angiotensin-converting enzyme (ACE), which was inspired from the tool of network pharmacology. METHODS: KEGG pathway enrichment of thymosin-α1 treating COVID-19 was analyzed by Database of Functional Annotation Bioinformatics Microarray Analysis, then core targets were validated by ligand binding kinetics assay and fluorometric detection of ACE and ACE2 enzymatic activity. The production of angiotensin I, angiotensin II, angiotensin (1-7) and angiotensin (1-9) were detected by enzyme linked immunosorbent assay. RESULTS: We found that thymosin-α1 impaired the expressions of angiotensin-converting enzyme 2 and angiotensin (1-7) of human lung epithelial cells in a dose-dependent way (p < 0.001). In contrast, thymosin-α1 had no impact on their ACE and angiotensin (1-9) expressions but significantly inhibited the enzymatic activity of ACE (p > 0.05). CONCLUSION: The bioinformatic findings of network pharmacology and the corresponding pharmacological validations have revealed that thymosin-α1 treatment could decrease ACE2 expression in human lung epithelial cells, which strengthens the potential clinical applications of thymosin-α1 to prevent severe acute respiratory syndrome coronavirus 2 infection.

Correlation between single-nucleotide polymorphisms and statin-induced myopathy: a mixed-effects model meta-analysis.

PURPOSE: A meta-analysis was performed to evaluate the correlation between single-nucleotide polymorphisms (SNPs) and risk of statin-induced myopathy (SIM). METHODS: We retrieved the studies published on SIM until April 2019 from the PubMed, Embase, and Cochrane Library databases. We collected data from 32 studies that analyzed 10 SNPs in five genes and included 21,692 individuals and nine statins. RESULTS: The analysis of the heterozygous (p = 0.017), homozygous (p = 0.002), dominant (p = 0.005), and recessive models (p = 0.009) of SLCO1B1 rs4149056 showed that this SNP increases the risk of SIM. Conversely, heterozygous (p = 0.048) and dominant models (p = 0.030) of SLCO1B1 rs4363657 demonstrated that this SNP is associated with a reduced risk of SIM. Moreover, an increased risk of SIM was predicted for carriers of the rs4149056 C allele among simvastatin-treated patients, whereas carriers of the GATM rs9806699 A allele among rosuvastatin-treated patients had a lower risk of SIM. CONCLUSION: The meta-analysis revealed that the rs4149056 and rs4363657 SNPs in SLCO1B1 and the rs9806699 SNP in GATM are correlated with the risk of SIM.

Pharmacokinetics, Safety, and Tolerability of Single- and Multiple-Dose Once-Daily Baricitinib in Healthy Chinese Subjects: A Randomized Placebo-Controlled Study.

The objective of this phase 1 study was to evaluate the pharmacokinetics, safety, and tolerability of baricitinib after single and multiple doses in healthy Chinese adults. Eligible subjects received a once-daily dose of baricitinib 2, 4, or 10 mg or placebo on day 1 (single dose) and days 4 through 10 for 7 consecutive days (multiple doses). Plasma pharmacokinetic samples were collected up to 48 hours after dosing on days 1 and 10, with predose samples collected before dosing on day 1 and days 4 through 10. Safety and tolerability were also assessed. Baricitinib was rapidly absorbed, reaching peak plasma concentrations within 0.5 to 1 hour (median). Plasma concentrations declined rapidly following the attainment of peak concentrations, with a mean terminal half-life of 5.7 to 7.3 hours. Steady-state plasma concentrations of baricitinib were achieved after the second day of once-daily dosing, with minimal accumulation of baricitinib in plasma (up to 10% increase in area under the plasma concentration-time curve). Single- and multiple-dose mean values for area under the plasma concentration-time curve from time zero to infinity and maximum plasma concentration appeared to increase in an approximately dose-proportional manner across the dose range. Single and multiple oral doses of once-daily baricitinib up to 10 mg were well tolerated by healthy Chinese subjects.

Precision and accuracy of commercial assays for vancomycin therapeutic drug monitoring: evaluation based on external quality assessment scheme.

BACKGROUND: Vancomycin remains a mainstay of the treatment of Gram-positive bacterial infections. It is crucial to accurately determine vancomycin serum concentration for adequate dose adjustment. OBJECTIVES: To evaluate the precision and accuracy of commercial assay techniques for vancomycin concentration and to assess the comparability of vancomycin detection methods in Chinese laboratories. METHODS: Human serum samples spiked with known concentrations of vancomycin were provided to laboratories participating in the external quality assessment scheme (EQAS). Assay methods included chemiluminescence, enzyme immunoassay (EIA) and so on. The dispersion of the measurements was analysed and the robust coefficient of variation (rCV), relative percentage difference (RPD) and satisfactory rate for method groups were calculated. Moreover, performance of the Chinese laboratories was assessed. RESULTS: A total of 657 results from 75 laboratories were collected, including 84 samples from 10 Chinese laboratories. The median rCV, median RPD and satisfactory rates classified by methods ranged from 1.85% to 15.87%, -14.75% to 13.34% and 94.59% to 100.00%, respectively. Significant differences were seen in precision, between kinetic interaction of microparticles in solution (KIMS) and other methods, and in accuracy, between enzyme-multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (FPIA) and other techniques. Vancomycin detection in China mainly depended on the chemiluminescence and EMIT methods, which tended to result in lower measurements. CONCLUSIONS: Although almost all assays in this study achieved an acceptable performance for vancomycin serum concentration monitoring, obvious inconsistencies between methods were still observed. Chinese laboratories were more likely to underestimate vancomycin concentrations. Thus, recognizing inconsistencies between methods and regular participation in vancomycin EQAS are essential.

Predicting ischaemic events using platelet reactivity in patients receiving clopidogrel: Indirect meta-comparison among VerifyNow, light transmission aggregometry and thromboelastography.

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)-VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended.

Balancing Dielectric Loss and Magnetic Loss in Fe-NiS2/NiS/PVDF Composites toward Strong Microwave Reflection Loss.

Lightweight, broad-band, and highly efficient microwave-absorbing materials (MAMs) with tunable electromagnetic properties are in high demand. However, the absorption properties are limited by the simple loss mechanism in commonly used absorbing materials. Here, we tested the microwave-absorbing properties of Fe-NiS2/NiS/poly(vinylidene fluoride) (PVDF) in the frequency range of 2-18 GHz. For the 2.5% Fe-NiS2/NiS/PVDF with the filling content of 20 wt %, the maximum reflection loss can reach -61.72 dB at 14.88 GHz, and the bandwidth can reach 3.8 GHz with the reflection loss value below -10 dB. Loss mechanisms of different composites were analyzed on the basis of their magnetic and dielectric properties using both experimental and computational methods. The results indicate that strong microwave absorption property is achieved through a balancing of dielectric loss and magnetic loss. These findings present a new strategy for the future design of MAMs.

Effect of pharmacist-led interventions on medication adherence and inhalation technique in adult patients with asthma or COPD: A systematic review and meta-analysis.

OBJECTIVE: In patients with asthma and chronic obstructive pulmonary disease (COPD), disease control is still suboptimal-incorrect inhalation technique and medication non-adherence are two important reasons for this outcome. Pharmacists' interventions have been shown to have a positive effect on the clinical outcomes of asthma and COPD. Quantitative assessment of the efficacy of pharmacist-led interventions, mainly on inhalation techniques and medication adherence, is needed. Evidence for different interventions is not totally conclusive, and no results of theory-based adherence promotion interventions for asthma and COPD have been published. The objective of our study is to evaluate the effect of pharmacist-led interventions on asthma and COPD management, focusing mainly on inhalation technique and medication adherence, and whether the content of interventions (categorized based on Information-Motivation-Behavioural skills (IMB) model) affects the effectiveness and whether the IMB model is worthy of clinical promotion and application in adults with asthma or COPD. METHODS: The PubMed, EMBASE, The Cochrane Library, Web of Science and ClinicalTrials.gov databases were searched for randomized controlled trials that involved pharmacist-led interventions among patients with asthma or COPD. We used database-specific vocabulary (eg, Medical Subject Headings) and free text terms expanding from 'asthma', 'COPD' and 'pharmacist' to identify relevant articles. Two reviewers independently selected the studies, assessed the risk of bias and extracted the data. The meta-analysis was performed in Review Manager 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019144793. RESULTS AND DISCUSSION: Thirteen studies were eligible for qualitative analysis, and 12 studies were included in the meta-analysis. Pharmacist-led interventions showed a positive effect on medication adherence (1.34 [95% CI 1.18-1.53], P < .0001) and inhalation technique (1.85 [95% CI 1.57-2.17], P < .00001) in COPD and asthma patients. In the subgroup meta-analysis, significant medication adherence improvement was found only in COPD patients (1.41 [1.24-1.61], P < .0001). The subgroup meta-analysis also noted that interventions that included all three Information-Motivation-Behavioural skills (IMB) constructs had a significant improvement in medication adherence (1.41 [1.24-1.61], P < .0001). Subgroup meta-analysis conducted between different diseases, different intervention contents, and different measure tools did not significantly change the heterogeneity. WHAT IS NEW AND CONCLUSION: Pharmacist-led interventions can improve inhalation technique in adult asthma and COPD patients. Significant improvement in medication adherence was found only in COPD patients. The effect among asthmatic patients requires further study. Interventions based on the IMB model may be worthy of clinical promotion and application. More future research is needed to establish solid evidence base for effective interventions and uniform measurement of medication adherence.

The impact of the clinical pharmacist-led interventions in China: A systematic review and Meta-Analysis.

Background The clinical pharmacist has been an important partner in clinical treatment team. In China, there is no systematic review to evaluate the effectiveness of clinical pharmacy services on patients' outcomes such as hospitalization days, readmission rate and mortality. Aim of the review To investigate the impact of clinical pharmacist services on patients' length of hospitalization, readmission and mortality in China. Methods A literature search was performed in PubMed, EMBASE, Cochrane Library, clinicaltrials.gov, and a Chinese database (up to January 2019). Randomized control trials or pre- to post-intervention comparison studies were included to investigate the impact of clinical pharmacist-led interventions on the length of stay, readmission rate and mortality of inpatients. Basic information, intervention and therapeutic area were extracted. Results After screening all articles from the mentioned databases, 14 studies were included for meta- analysis and subgroup analysis. Most studies focused on cardiology and respiratory diseases. Results show that clinical pharmacist services can reduce the length of stay of inpatients (MD: - 3.00, 95% CI - 4.72 to - 1.29, P < 0.01) and the readmission rate (RR 0.44, 95% CI 0.35-0.56, P < 0.01) as well as the mortality of patients during hospitalization (RR 0.57, 95% CI 0.35-0.92, P = 0.02). Conclusions Clinical pharmacist-led interventions could significantly reduce Chinese patients' length of hospitalization and readmission rate. More studies are needed to confirm the relationship between the clinical pharmacist-led interventions and patients' mortality.

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities.

December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.

Population pharmacokinetics of cyclosporine A in Chinese patients with nephrotic syndrome in individualized drug administration
.

OBJECTIVE: To establish a population pharmacokinetic (PopPK) model of cyclosporine A (CsA) in Chinese patients with nephrotic syndrome (NS) and to use the model to guide the adjustment of individualized dosage regimens. MATERIALS AND METHODS: 216 CsA therapeutic drug monitoring (TDM) concentration observations were collected from 127 Chinese patients with NS. The basic model was developed as a one-compartment PK model with first-order absorption and linear elimination. The first-order conditional estimation (FOCE) method was applied to establish the final model with covariates using NONMEM software. The final model was evaluated through internal validation including goodness-of-fit analysis and bootstrap method as well as external validation using 39 additional PK observations from 35 patients with NS. RESULTS: A PopPK model of CsA was established in Chinese NS patients with influence of body weight on clearance. The internal and external validation results showed that the final model was stable. CONCLUSION: The established population model adequately characterized the PK of CsA in Chinese patients and could support individualized medication during treatment of NS with CsA.

Safety, pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers.

PURPOSE: The aim of the present study was to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of remimazolam besylate following single ascending dose (SAD) and continuous infusion in healthy Chinese volunteers. METHODS: This was a randomized phase I study conducted in two parts. Part I was a double-blind, placebo- and midazolam-controlled, SAD study among healthy Chinese participants with a remimazolam dose of 0.025-0.4 mg/kg. Part II was an open-label, midazolam-controlled, continuous infusion study. Bispectral index (BIS) monitoring and Modified Observers Assessment of Alertness and Sedation (MOAA/S) score assessment were used to assess the PD properties. RESULTS: The half-life range of remimazolam was from 34.1 ± 8.1 to 59.8 ± 20.5 min in the SAD study. The sedation function was initially observed at the dose of 0.05 mg/kg remimazolam. Doses of ≥ 0.075 mg/kg exerted a peak sedation effect within 1-2 min after injection, resulting in a deeper and more rapid sedation. In the 2 h continuous infusion, remimazolam showed a deeper sedation and more rapid recovery than midazolam. For general anesthesia, an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h can achieve a satisfactory efficacy effect. CONCLUSIONS: Remimazolam was safe and well tolerated in healthy Chinese participants. Based on the phase I clinical study, we suggest that remimazolam besylate demonstrates greater sedation and quicker recovery from sedation than midazolam.

The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: A meta-analysis.

AIMS: The aim of the present meta-analysis was to evaluate the efficacy and safety of fingolimod in patients with relapsing multiple sclerosis (RMS). METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for relevant studies. Two authors independently selected the studies, assessed the risk of bias, and extracted the data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. RESULTS: Ten studies met the inclusion criteria. In patients with RMS, fingolimod demonstrated a significantly lower annualized relapse rate (0.5 mg/d: mean difference [95% confidence interval] = -0.22 [-0.29 to -0.14]; 1.25 mg/d: -0.26 [-0.36 to -0.16]; 5 mg/d: -0.41 [-0.72 to -0.10]) than placebo. Fingolimod also exhibited a favorable performance on other magnetic resonance imaging outcomes and improved the quality of life in patients. No significant difference was noted in the prevalence of adverse events between the fingolimod treatment group and the placebo/disease-modifying therapy groups. CONCLUSIONS: Fingolimod may offer benefits for RMS patients and presents an acceptable safety profile.