ArchiveThe aim of the article was to study the difficulties that Chinese drug manufacturing enterprise (hereinafter referred to as drug enterprise) may face after the official implementation of electronic common technical document (eCTD), and to propose countermeasures. The origination, development and global implementation of eCTD were introduced, as well as the relevant guidelines issued by NMPA, so as to analyze the possible problems in the process of eCTD registration application of drug enterprise in China and put forward relative countermeasures. eCTD has been widely used in the world. The eCTD guidelines published in China was established based on V3.2.2 version issued by ICH. eCTD helps to improve the efficiency of drug application but is difficult to develop and has high professional requirements. It is advisable for drug enterprise to make early planning, complete the construction of eCTD registration application system as soon as possible, and prepare the arrival of the eCTD era with a positive attitude.
New drug R&D typically holds the characteristics of high technical barriers of entry, requiring high monetary spending, long cycle of development, multidisciplinary, and carrying high risk and high added value. Formulating and optimizing new drug R&D strategy is of great significance to the survival and development of pharmaceutical enterprises. The problem of absence of new drug strategic management is pervasive in the process of innovation and transformation of Chinese pharmaceutical enterprises. Through analyzing the cases of leading enterprises in the industry and exploring the methods to formulate and optimize the management of R&D strategic planning and its implementation, the author is dedicated to the benefit of domestic enterprises to promote and develop low-cost, high-quality new products with clinical and commercial value, aiming to improve China's influence and competitiveness in the field of innovative drugs.
To explore the elements that influence the behavior choices and the feasibility of delegated manufacturing of traditional Chinese medicine preparations in medical institutions under the marketing authorization holder (MAH) system.
A tripartite evolutionary game model of MAH, trustee, and government was built, the tripartite strategy choices in the process of entrusted manufacturing of preparations were analyzed, and simulation analysis was conducted to investigate the influencing factors of strategy choice.
Considering the interest demand and the risk degree, keeping the appropriate subsidy and penalty intensity can help to improve the enthusiasm of MAH and trustee. The government's initiatives to boost rewards and penalties will help to improve MAH and client engagement in commission allocation, but too many rewards and penalties will conflict with the government's regulatory responsibilities. The social loss caused by the government's non-supervision urges the government to improve the supervision rate.
Entrusted manufacturing of traditional Chinese medicine preparations is feasible. Finding the point of profit balance among stakeholders helps to actualize the beneficial cycle of traditional Chinese medicine preparations in medical facilities.
To scientifically construct the evaluation indicators for human use experience of traditional Chinese medicine (TCM) and provide reference for the formation of "triple combination" registration review evidence system.
Based on the Delphi method, after literature research and expert investigation, two rounds of expert consultation were carried out, and the expert consultation results were evaluated by the mean, variation index, coordination coefficient, etc., and the core indicators for human use experience evaluation of TCM were further screened and optimized.
22 experts in various fields were selected to conduct a questionnaire survey. The participation rates of experts in the 2 rounds of consultation were 100% and 95.46%, and the authority indicators of involved experts were 0.852 and 0.865. According to the mean value and coefficient of variation of the indicators, combined with the revision suggestions of experts, the core indicators of human use experience evaluation including 4 first-level indicators and 22 second-level indicators were finally formed.
The core indicators for human use experience evaluation of TCM could guide the standardized collection and summary of human use experience data, promote the formation of high-quality and evaluable human use experience evidence, and support the research and development of new TCM products.
Since 2015, a series of policies implemented by China's drug review and approval reform have built a good ecological environment for the development of innovative drugs in China. The development of innovative drugs in China has achieved initial results. In recent years, with the increase in the number of pre-approval inspection tasks for innovative drugs, prominent problems such as unclear responsibilities between drug registration applicants and entrusted units, imperfect quality management systems and many GMP observations were found in the pre-approval inspections according to the verification standards such as the "pre-approval inspection procedures" and the "main points and judgment principles on pre-approval inspection". This paper studied the characteristics of the innovative chemical drugs, sorted out the basic situation of the innovative chemical drugs, summarized and analyzed the main problems found in the pre-approval inspection of innovative chemical drugs from 2019 to 2021, and put forward corresponding suggestions, in order to provide reference for the research and development and registration of new drugs in the industry and provide reference for pre-approval inspection of innovative drugs.
Tissue repair is a process that involves coagulation reaction, inflammatory reaction, cell proliferation and remodeling induced by tissue injury. Bletilla striata is a traditional Chinese medicine with astringent and hemostatic effect. Its extract has pharmacological effects such as hemostasis, anti-inflammatory effect, antibacterial and antioxidant effect, so that it can promote tissue repair and reconstruction. This paper reviews the extract and pharmacological mechanism of Bletilla striata in tissue repair and reconstruction, so as to provide reference for its clinical medication and expand the scope of clinical application.
Tumor immunotherapy holds immense potential for tumor treatment because it can utilize the patient's immune system to eradicate tumors and prevent tumor recurrence. Nanoparticles are expected to be the optimal carrier for tumor immunotherapy due to their unique advantages. Ca2+, as the second messenger in cells, plays an important role in regulating the immune response in vivo. Recent studies have shown that calcium nanoparticles, such as calcium peroxide (CaO2) nanoparticles, calcium phosphate (CaP) nanoparticles, calcium hydride (CaH2) nanoparticles and calcium carbonate (CaCO3) nanoparticles, can activate anti-tumor immune responses through a variety of mechanisms. In addition, calcium nanoparticles can also be used in combination with other therapies such as photothermal therapy (PTT), sonodynamic therapy (SDT), chemotherapy and radiotherapy to synergically fight tumors to exert the "immune+" anti-tumor effect. In this article, we reviewed the recent research progress of calcium nanoparticles in tumor immunotherapy, and looked forward to the challenges of this field.
Endocrine therapy is one of the treatment options for estrogen receptor-positive breast cancer. The therapeutic drugs include selective estrogen receptor modulators, selective estrogen receptor down-regulators and aromatase inhibitors. The resistance of tumor cells to endocrine therapy is one of the key factors limiting the clinical application of endocrine therapeutic drugs. Resistance includes intrinsic drug resistance and acquired drug resistance. The generation of acquired drug resistance may be related to the overexpression of ERα coactivators and the abnormal expression of cell cycle regulators mediated by ER, RTKs, PI3K and other pathways. This article mainly reviews the mechanism of breast cancer resistance to endocrine therapy and the treatment strategies.
Tuberculosis infection has always been a major concern for rheumatologists. The treatment of diseases such as spinal arthritis has entered the era of biologics, but the use of biologics will increase the risk of opportunistic infections such as tuberculosis. As a novel biological agent, secukinumab can improve the prognosis and quality of life of patients with ankylosing spondylitis and psoriasis by blocking the effect of IL-17A and playing an immunomodulatory function. This article reviews the safety of secukinumab in terms of tuberculosis infection in order to provide reference for clinical application.
To evaluate the anesthetic effects of remimazolam in total intravenous anesthesia (TIVA) patients undergoing radical thyroidectomy.
Patients aged 18~65 with ASA physical status Ⅰ~Ⅱ were scheduled for radical thyroidectomy under TIVA. The current study consisted of two parts. Part Ⅰ: The anesthetic induction dose of remimazolam was determined using modified Dixon's up-and-down method. Part Ⅱ: The effect of remimazolam in anesthetic maintenance of TIVA was evaluated. The patients were randomly divided into two groups, propofol as control P group and remimazolam as experimental R group. After endotracheal intubation, propofol or remimazolam was continuously infused under TIVA to complete surgery. The onset time, intubation time, drug consumption and hemodynamics at certain time points were analyzed. In addition, the awakening time and adverse effects were also compared. The cognitive functions were evaluated by scale of MMSE and MoCA.
The anesthetic induction doses of propofol and remimazolam were 1.76 mg·kg-1 and 0.43 mg·kg-1 respectively. The onset time of the two groups had no significant difference (P>0.05). However, the intubation time of remimazolam group (103.23±9.14) s was significantly increased than that of the control group (86.58±8.32) s (P<0.05). The mean pump speed of remimazolam was 1.12 mg·kg-1·h-1 in TIVA. The hemodynamics of remimazolam group [MAP: (88.2±8.4) mmHg; HR: (74.2±7.1) per minute] was more stable than that of the control group [MAP: (77.9±7.4) mmHg; HR: (68.8±6.5) per minute] (P<0.05). The awakening time of remimazolam group (19.31±4.26) min was enhanced compared with the control group (13.86±3.65) min (P<0.05). The adverse effects and cognitive functions of the two groups had no statistical differences (P>0.05).
Remimazolam is safe for clinical anesthetic induction and intraoperative maintenance undergoing radical thyroidectomy, and the hemodynamics is more stable in TIVA.
To analyse and predict the potential quality markers of Aurantii fructus immaturus which based on HPLC fingerprint, chemical pattern recognition, the "Five Principles" of quality markers and network pharmacology.
The fingerprint of Aurantii fructus immaturus was established by HPLC; OPLS-DA was used to screen the main difference components among the common peak groups; the "active ingredient-target-pathway" network of differential components was constructed by network pharmacology method to further support its rationality as potential quality makers (Q-Marker) of Aurantii fructus immaturus.
The fingerprints of 22 batches of Aurantii fructus immaturus were established, and 36 common peaks were identified. Two different components of naringin and neohesperidin were screened by OPLS-DA analysis. Network pharmacology confirmed that naringin and neohesperidin can be used as potential Q-Markers of Aurantii fructus immaturus.
The established HPLC fingerprint method is stable and feasible, and the two differential components of naringin and neohesperidin screened can be used as potential Q-Markers of Aurantii fructus immaturus, which provided reference for the quality control and pharmacological mechanism research of Aurantii fructus immaturus.
To probe the effects of high-altitude hypoxia environment on the pharmacokinetic parameters of metformin after multiple administration in type 2 diabetes mellitus (T2DM) rats.
Liquid chromatography-mass spectrometry (LC-MS/MS) was used, separation was conducted by a Gemini C18 (75 mm×3 mm, 3 μm) column, the mobile phase was acetonitrile-water-formic acid (85∶15∶0.1, v/v/v), the flow rate was 0.4 mL·min-1, the injection volume was 2 μL, and the internal standard was ranitidine. T2DM rats were randomly divided into plain group and plateau group, and were given continuous gavage once a day for 7 days, and on the 7th day blood samples were collected before administration and at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24 h after administration for determination of drug concentration. The DAS 2.0 software was used to simulate and fit the plasma concentration-time data to calculate the pharmacokinetic parameters.
Compared with the rats in the plain group, the peak time (Tmax), clearance rate (CLZ/F) and average residence time (MRT) of metformin were prolonged by 29.03%, 33.25% and 44.98% (P<0.05) in the rats under high-altitude environment, respectively. The AUC increased by 46.22% (P<0.01).
The elimination of metformin is slowed down in T2DM rats after multiple administration under high-altitude hypoxia environment.
To illustrate the overall differential material basis of three kinds of Ge-Gen Decoction (GGD) granules including Ge-Gen Decoction compound granules (CG), formula granules (mixed, FGm; decocted, FGd) and Kampo granules (KG) using UHPLC-Q-TOF-MS combining with multivariate statistical methods.
AcclaimTM RSLC120 C18 chromatographic column (100 mm×2.1 mm, 2.2 μm) was employed to separate chemical compositions and gradient elution was performed with 0.1% formic acid-acetonitrile as mobile phase. ESI ion source was used to collect data in positive and negative ion modes respectively. The data were imported into SIMCA-P software for principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Student's t-text was utilized to measure the significance values of each metabolite. The m/z of differential components were filtered according to P<0.05, VIP>3. Then, HMDB, PubChem, TCMSP, MassBank database, MS/MS ion fragments, and related references were utilized to analyze qualitatively the differential components. Finally, combining with semi-quantitative data, a comprehensive characterization for the differential components of the three GGD granules was described.
There were 40 differential components between CG and KG, and the contents of most chemical components were higher in CG at the same dose. A total of 49 differential components were identified between CG and FGm. Some of the main active components such as puerarin and ephedrine had higher contents in CG. There were 45 differential components between FGm and FGd and there was no new component detected. The contents of most components increased after decocting. However, some important components in Paeoniae Radix Alba formula granules decreased. Fifty-nine differential components were detected totally in three kinds of Ge-Gen Decoction, and they mainly varied in the relative content, not the types. Puerariae Radix had the largest number of differential components.
UHPLC-Q-TOF-MS method can rapidly identify different components of three Ge-Gen Decoction granules, providing data support for the preparation process of Ge-Gen Decoction granules and laying a foundation for the quality control and clinical application of formula granules.
To explore the clinical characteristics and treatment strategies of central nervous system adverse events induced by atezolizumab to provide reference for recognition and treatment of such events.
Non-review articles on central nervous system adverse events caused by atezolizumab were screened, and relevant cases were summarized and analyzed. Furthermore, a case of anti-SOX1 paraneoplastic neurological encephalitis induced by atezolizumab in our hospital were discussed in combination with literature.
Atezolizumab-induced central nervous system adverse reactions have been reported, but anti-SOX1 paraneoplastic neurological encephalitis was reported for the first time. Autoimmune antibody test had reference value for clinical diagnosis of this case. And simultaneous steroid pulse therapy and plasmapheresis were performed, leading to ideal clinical outcome.
The nervous system manifestation of patients using atezolizumab should be closely monitored pre and post treatment and clinicians should be alert to the occurrence of paraneoplastic encephalitis. The relevant autoantibodies should be systematically evaluated in times of need.
To study venous thromboembolism associated with risperidone in the treatment of schizophrenia, so as to provide references for future clinical rational drug use.
A case of risperidone-associated pulmonary thromboembolism was presented and the cases of risperidone-associated venous thromboembolism, deep vein thrombosis and pulmonary thromboembolism were collected from Chinese VIP journal database, Wanfang and PubMed database and analyzed.
A total of 13 cases were retrieved. Risperidone-induced venous thromboembolism has been reported in all age groups, and the dose ranged from 1 to 6 mg. Adverse reactions occurred within 2 months after the medication (10/13 cases), and the clinical manifestations were mainly respiratory symptoms or symptoms related to lower limb venous thromboembolism, such as lower limb edema and pain. Severe cases led to syncope, cardiopulmonary arrest or even death.
Clinicians and pharmacists should be familiarized with the characteristics of pulmonary thromboembolism associated with risperidone, weigh the advantages and disadvantages, and use it with caution. To reduce the occurrence of adverse reactions, coagulation function monitoring and venous ultrasound examination of lower limbs should be strengthened, and CT pulmonary angiography should be performed if necessary.