ArchiveBy combing the relevant policies of national and local orphan drug security policy, this paper analyzed the current situation of orphan drug security policy in China from the perspective of drug life cycle, and puted forward corresponding countermeasures and suggestions. In this paper, by consulting the relevant literature, searching the national and local government websites and the network platforms of rare disease-related organizations, combed the policies in the stages of drug research and development, registration, pricing and reimbursement, supply, post-market supervision (drug vigilance) and diagnosis and treatment of rare diseases from 2015 to 2020. In the past five years, the state and various ministries have issued a series of orphan drug protection policies, as well as some provinces and cities issued some orphan drug reimbursement policies, but there is no search for China's special post-market supervision policy for orphan drugs. It is suggested that under the premise of multi-sector cooperation, our country can set up full-time departments for rare diseases and orphan drug protection to provide diversified protection measures for patients with rare diseases.
This paper gives an empirical research on the relationship between the regional level of pharmaceutical economic development and R&D investment of the pharmaceutical manufacturing industry in the eastern, central and western regions of China to provide reference for improving the innovation level of pharmaceutical manufacturing industry and the development level of regional economy. The relevant data from 1995 to 2016 were selected based on the co-integration theory, and the Granger causality test was conducted to analyze the influence between the two. The result indicates that the level of pharmaceutical economic development in eastern, central and western regions of China has a positive impact on the R&D input intensity of the pharmaceutical manufacturing industry. The degree of the impact in western region is higher than in eastern region, and the central region is the lowest. Finally, this paper suggests the government should provide policy guidance, rational allocation of resources and financial support according to regional differences, and each region should utilize its own advantages to promote regional pharmaceutical economic development, so as to improve the innovation level of pharmaceutical manufacturing industry.
Reference standards are important material basis for drug control, meanwhile legal distribution of the national drug reference standards is one of the basic functions of NIFDC. A reform of distribution model for reference standard has been carried out by NIFDC in 2019, which changed the past two-level distribution and fully implemented direct distribution to users. Some key points are applied by NIFDC who faces the increasing workload and strict quality control requirements, including adjusting process links, establishing distribution traceability system, founding 9 steps of packaging procedure, building limitation of transportation and so on. As a result, smooth transition to direct distribution was realized. In order to provide guidance to improve the efficiency of reference standard management, this article summarizes the methods of efficiency improvement, analyzes the strategies of quality control, and combs the process nodes. In addition to the above points, some conclusions are made, such as the foundation to direct distribution was providing resources effectively, the powerful tool was intelligent external distribution platform, the significant guarantee was training and guiding users to order correctly.
To summarize the indexes of juvenile SD rats in control group of the 4-week repeated administration toxicity test in our laboratory, and to establish the background data of our laboratory so as to provide reference for the evaluation of non-clinical safety of pediatric drugs.
From repeated administration toxicity test of pediatrics between 2015 and 2019, the indexes of juvenile SD rats were selected and analyzed, including body weight, feed consumptions, reproductive development (preputial separation and vaginal patency), skeletal development (crown-rump length, tibia length and bone density), hematology, blood biochemistry, immunization and viscera index.
The mean value, standard deviation, maximum and minimum values, 95% confidence interval as well as coefficient of variation of all indicators from juvenile SD rats in different genders were obtained through statistical analysis.
The reference ranges of normal values of juvenile SD rats for different genders and ages were established.
To develop a cell-based reporter gene assay (RGA) for bioactivity determination of anti-EpCAM+CD3 bispecific antibody (BsAb).
A HcT116-Luc cell line stably expressing Luciferase (Luc) was generated as the target cell, and a HuT78 cell line served as effector cell. The RGA was established by optimizing the initial concentration of BsAb, incubation time, cell seeding time, the ratio of effector cell to target cell, and cell seeding density. The specificity, accuracy, precision, linearity, subculture stability and robustness of RGA were verified according to the guideline of International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q2 and Pharmacopoeia of the People's Republic of China (ChP, 2015).
The parameters of RGA were developed and confirmed after optimization as follows: The ratio of effector cell to target cell was 10∶1; After mixing effector cell and target cell, the mixed cells were seeded in 96-well plate with 1.1×104 cells·well-1, which was cell seeding density; The initial concentration of BsAb, 3 000 ng·mL-1, was serially diluted by 1∶3.5 for 9 gradients, and there were 10 detected concentrations in all; The serially diluted samples were incubated for 72 h with the seeding cells. After the incubation, the Luc intensity was measured, and the dose-response curve was fitted in a 4-parameter mode to calculate the relative bioactivity of sample. The accuracy, precision and linearity verification were performed by 8 potency concentrations, which were 50%, 70%, 80%, 100%, 120%, 130%, 150% and 200% potency concentrations. The recovery rate range of relative bioactivities of 8 potency concentrations was 95.48%~107.37%, and the coefficient of variation (CV) ranged 4.80%~9.97%, which was <10%. The measured potency to expected potency was evaluated by linear regressing model analysis (r2>0.99). The Luciferase was stably expressed in HcT116-Luc cell between 14 and 33 passage.
Based on passage cells, the RGA has been developed as a simple and convenient procedure for determination of bioactivity of anti-EpCAM+CD3 BsAb, and its specificity, precision, accuracy and robustness met the application requirements.
The management strategies for drug clinical trials under major public health emergencies were discussed from the perspectives of measures taken for epidemic prevention and control as well as clinical trial quality assurance. Facing major public health emergencies, clinical trial institutions should take preventive and control measures in accordance with relevant regulations. It was necessary for ethics committees, investigators and sponsors to take use of any approaches to minimize the impact on trial quality. A major public health emergency is the challenge to emergency response capability for drug clinical trial institutions. Relevant practitioners need to promote cooperation among all parties by transforming their thinking modes so as to improve comprehensive management skills.
Immune checkpoint inhibitors (ICPis), a kind of monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. Unfortunately, ICPis have also been associated with the emergence of a new subsets of autoimmune-like toxicities, known as immune-related adverse events (irAEs). Acute kidney injury (AKI) is one of the common irAEs. This paper reviews the clinical manifestations, incidence, risk factors, mechanisms and treatment of ICPi-induced AKI. The risk of ICPi-induced AKI is significantly higher than that induced by chemotherapeutic drugs, and the involved risk factors include the type of ICPi drug and the proton pump inhibitors (PPIs). The typical symptom of ICPi-induced AKI is increased serum levels of creatinine and pyuria. The typical histopathological features are acute tubulointerstitial nephritis (ATIN). During ICPi treatment, renal function should be closely monitored to detect and intervene AKI early. The main treatment is glucocorticoid therapy, and immunosuppressive drugs can be added when necessary. This study provides reference for the clinical safety application of ICPi in China with a view to improve the prognosis of cancer patients and make them more beneficial.
An HPLC-MS/MS method was developed for simultaneous determination of dexrabeprazole and levrabeprazole concentrations in human plasma by using a chiral chromatographic column. It was used in the pharmacokinetic study of dexrabeprazole sodium for injection.
AB Sciex API4000 liquid-mass spectrometer with ESI ion source was selected and the Daicel CHIRALPAK® IC (250 mm×4.6 mm, 5 μm) chiral chromatographic column were used with the mobile phase of acetonitrile-10 mm ammonium acetate (75∶25, v/v) at a flow rate of 1 mL·min-1. The isotopic [2H3]-dexrabeprazole was used as internal standard. The plasma samples were analyzed using 2 μL supernatant after the protein was precipitated by acetonitrile. Forty healthy volunteers participated in the pharmacokinetic study of dextrorabeprazole sodium for injection.
The established HPLC-MS/MS method has good linear relationship for dexrabeprazole in the range of 1.00~1 500 μg·L-1, and for levrabeprazole in the range of 1.50~1 500 μg·L-1. The results show that the linearity, selectivity, lower limit of quantification, precision and accuracy, recovery, matrix effect as well as stability all meet the test requirements.
The HPLC-MS/MS method established in this laboratory has strong selectivity, high sensitivity and good chiral separation. It is suitable for the concentration determination of dexrabeprazole and levrabeprazole in human plasma, and has been successfully applied to the pharmacokinetic study of dexrabeprazole sodium for injection.
With coronavirus disease 2019 (COVID-19) spreading, the rhythm of clinical trials has been challenged. Based on the guidelines and relevant regulations of clinical trials during the epidemic period, the Drum Tower Hospital Affiliated to Nanjing University School of medicine has designed a survey to investigate the current situation of clinical trials. Association, CRA, clinical research coordinator (CRC), and test managers were involved in the research. According to the survey results, most researchers reflected that the progress of clinical trials was affected (68.24%), and the clinical trials of non-oral drugs were greatly affected (69.96%), which was mainly manifested in the malignant tumor project (88.2%), during the trial, the most obvious influence is 92.7% for out of visit window, and the subject worrying about the deterioration of disease (78.97%), the risk of drug overtemperature exists in mailing drugs (60.09%), and the number of trials timeliness (89.09%) and integrity (79.61%) were the most affected. Therefore, it is a new working mode for our clinical trial institutions to improve the emergency mechanism of clinical trials, strengthen the supervision of trials, and realize the sharing of clinical trial data and the whole process information management.
To assess the protective effect and mechanism of mosloflavone against heart damage induced by hypobaric hypoxia (HH) in mice.
60 male BALB/c mice were randomly divided into four groups: control group, hypoxia group, rutin group and mosloflavone group. The mice were orally treated for 5 days with drugs or water and then exposed to HH equivalent to 8 000 m for 12 h. Serum concentrations of lactic dehydrogenase (LDH), creatine kinase (CK), aspartate transaminase (AST) and cardiac troponin I (cTnI) were assessed. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH), as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and ATPase, in heart were estimated. The expression of Bax and Bcl-2 were evaluated by Western blot analysis.
Compared with control group, the levels of LDH, CK, AST and cTnI in serum in hypoxia model group significantly increased. In addition, HH markedly increased the contents of ROS and MDA and decreased the GSH contents and the activities of SOD, CAT, GSH-Px and ATPase in heart. Furthermore, HH significantly unregulated the expression of Bax and downregulated the expression of Bc1-2. In contrast, mosloflavone alleviated heart damage induced by HH as evidence of reduced LDH, CK, AST and cTnI levels in serum. Prior administration of mosloflavone also decreased the ROS and MDA contents, increased GSH level, SOD, CAT, GSH-Px, Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities, downregulated the expression of Bax, as well as increased the expression ratio of Bax/Bc1-2 in heart tissue of mice.
Mosloflavone exhibited protective effect against HH induced heart injury in mice via alleviating of oxidative stress, ameliorating of energy metabolism, as well as regulating of apoptosis related proteins.
A prediction model for the granule growth profiles in fluidized bed of traditional Chinese medicine was developed to improve the research and development of traditional Chinese medicine preparation technology from laboratory trial and error to scientific, digital and intelligent mode.
The basic working conditions of the fluidized-bed top spray granulator were constructed by SolidWorks Premium software, and the grid was then divided by ANSYS ICEM CFD software. Computational fluid dynamics (CFD) was used to establish the mathematical model of granules agglomeration. The agglomeration mechanism rules were customized and the user-defined functions were cooperated into the model. The established CFD model was used to simulate the granulation process of Lysimachia christinae Hance extract and Sedum sarmentosum Bunge extract in a fluidized bed respectively. Furthermore, the fluidized bed granulation experiments were carried out to verify the accuracy of the model.
The simulation results showed that the particle size of the granules increased with the increasing simulation time, and the particle size distribution gradually widened. The velocity of the particles and the pressure of the mixed phases in the bed changed due to the particle growth. The experimental results of granules size growth rate and spatial distribution were in good agreement with those of numerical simulation.
The simulation of granule growth trend can be used to predict or judge the appropriateness of the formulation process and is helpful to effectively control the key quality attributes of the final granules.
To develop the first batch of standardized reagents for the potency assay of heparin, low-molecular-weight heparin (LMWH) anti-factor Xa and anti-factor Ⅱa.
Fibrinogen coagulation method was used for factor Ⅱa reagent to assign the potency, which was calculated with the national standard of thrombin. Chromogenic substrate method was used for antithrombin Ⅲ to assign the potency, which was calculated with the WHO international standard. The potency of facor Xa was measured using a fully automatic hemagglutination instrument, calculated with the national standard of human coagulation factor. The purity and free pNA content of chromogenic substrates S-2765 and S-2238 were analyzed by reversed-phase chromatography. The separation was obtained by the column Agela Technologies Venusil XBP RP C18 (250 mm×4.6 mm, 5 μm) using mobile phase A of 20% acetonitrile solution which contained 0.1% trifluoroacetic acid and phase B of 60% acetonitrile solution which contained 0.1% trifluoroacetic acid in a gradient elution. The wavelength was set at 313 nm. The constant Km was calculated to evaluate the enzyme and substrate affinities.
The standard reagent potency of factors Ⅱa, Factor Xa, and Antithrombin III were 40 IU, 76.3 nKat, and 10 IU per vial, respectively. The limit of quantification (LOQ) and detection limit of detection (LOD) of pNA were 7.6 ng·mL-1 and 2.3 ng·mL-1; the linear range is 0.005~100 μg·mL-1(r=1.0); the sample recovery rate is in the range of 98.5%~102.3%. The contents of chromogenic substrates, S-2765 and S-2238, are 96.2% and 97.3%. There is no statistical difference in Km between imported reagents and standard reagents.
According to the quality test results of standard reagents in this study, it can be seen that standard reagents can completely replace imported reagents, and the value of standard reagents is much accurate compared to imported reagents.
To systematically evaluate the effectiveness, safety and economics of taurodeoxycholic acid (TUDCA) in the treatment of cholelithiasis based on the health technology assessment (HTA) method.
The HTA reports, systematic reviews, randomized controlled trials and pharmacoeconomic researches were retrieved from PubMed, Embase, Cochrane Library, CNKI and Wanfang databases, as well as the HTA organization databases and websites. A Meta-analysis or descriptive analysis on the search results were performed.
Four RCT studies and one economic study were included in this study. The literature is generally of good quality. Compared with ursodeoxycholic acid (UDCA) or placebo, after TUDCA treatment for 3 to 4 months, the apparent efficiency rate was higher than the control group [RR=3.60, 95%CI (1.56 to 8.29), P=0.003], and the effective rate was also higher than the control group [RR=5.24, 95%CI (2.67~10.26), P<0.000 01], the inefficiency rate is lower [RR=0.19, 95%CI (0.10~0.37), P<0.000 01]. Compared with UDCA, the apparent and total effective rates were slightly higher than those in the control group after 6 months of treatment with TUDCA [RR=1.54, 95%CI (0.88~2.72), P=0.13] and [RR=1.66, 95%CI (0.93~2.96), P=0.09], the treatment inefficiency was lower [RR=0.60, 95%CI (0.34~1.08), P=0.09]. TUDCA has a good safety without serious adverse reactions occurred during the treatment. For patients with non-surgical cholelithiasis, TUDCA is expensive (ΔC=3 876.08), but more effective than UDCA (ΔE=24.98%, ICER=15 504.32). Compared with the UDCA, TUDCA has an absolute economic advantage in preventing gallstone recurrence (△C=-1 742.05) and incremental output (△U=0.22 QALYs, ICER=-7 975.26 yuan/QALD).
TUDCA has good efficacy and safety in treating cholelithiasis. Compared with UDCA, TUDCA was relatively more cost-effective in treating cholelithiasis. Since only 4 studies comparing TUDCA with UDCA or placebo were included, the results of this study are at risk of bias due to the small sample size and limitations of the research methods.
To analyze the security alert signals of olanzapine after marketing by big data mining, and to provide references for rational clinical drug use.
The adverse drug events (ADE) of olanzapine since Jan, 2014 were retrieved based on the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database utilizing the Open Public Data project of FDA (openFDA). The signals were detected by reporting odds ratio (ROR), and the lower bound of 95% confidence interval (ROR 95% CILower bound) >1 was regarded as the suggestion of security alert signals. The disproportionality analysis results of alert signals for olanzapine vs. other antipsychotic drugs (including quetiapine, clozapine, risperidone, perphenazine, aripiprazole, ziprasidone, chlorpromazine, perphenazine, and haloperidol) were compared, and the highest relative reporting ratio (RRR) indicated the drug were the most probably related with the alert signal.
A total of 11 171 211 reports were retrieved, among which there were 27 705 ADE reports that were suspected to be caused by olanzapine. The number of reports and signals referring to psychiatric disorders were the highest. The ADE signals that were above 1 000 cases included toxicity to various agents, drug ineffective, drug interaction, weight increased, somnolence, completed suicide, overdose, and neuroleptic malignant syndrome (NMS). Among the top 100 ADE signals, a total of 83 security alert signals were detected by ROR, among which sixteen alert signals were not mentioned in the latest label of olanzapine, and the NMS showed the highest risk (ROR 95% CILower bound=58.227). The risk relevance of chlorpromazine (RRR=75.271) and haloperidol (RRR=66.164) in the case of NMS were both greater than that of olanzapine (RRR=52.375).
It can effectively provide reference for future pharmacovigilance work to detect and analyze the security alert signals of olanzapine using openFDA platform.
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