Latest ArticlesGlucagon-like peptide-1 (GLP-1) analogues have been widely used in the treatment of diabetes and obesity, and multi-receptor agonists that combine GLP-1 analogues with other intestinal hormones such as glucose-dependent insulin-stimulating peptide (GIP) and glucagon (GCG) are in clinical development. Compared with GLP-1 analogues, multi-receptor agonists can exert multiple physiological effects and have better effects in controlling blood glucose and reducing body weight with fewer side effects, which are expected to be a new therapy for diabetes and obesity. In this paper, we reviewed the development of intestinal hormone multi-receptor agonists, summarized their design ideas and clinical manifestations, and provided reference for the development of multi-receptor agonists.
With the rapid research and development of cellular therapy products, new stem cell-derived cellular therapy products are constantly being developed, but only few relevant guidance documents to assist the design of studies for non-clinical safety evaluation have been published. Stem cell-derived cellular therapy products not only come from different sources, but also have different safety factors and potential risks of ectopic tissue formation, uncontrolled biological distribution, immunogenicity and tumorigenicity, etc. Different stem cell-derived cellular therapy products bring great challenges to non-clinical studies. The paper gives a brief overview of the types of stem cells and general principles for the non-clinical safety evaluation of stem cell-derived cellular therapy products, focusing on the animal selection, experimental design and tumorigenicity study, in order to provide some references for non-clinical safety evaluation of stem cell-derived cellular therapy products in China.
Toxicologic pathology is one of the most valuable disciplines contributing to the advancement of animal and human health. The gold standard of the toxicologic pathology evaluation in toxicity studies during nonclinical safety evaluation of drugs is considered to be the histopathological examination of paraffin-embedded, hematoxylin and eosin-stained tissue sections. Digital toxicologic pathology, artificial intelligence (AI), and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the field of histopathology is quickly being realized. The development and application of increasing numbers of algorithms in the histopathological field have demonstrated that AI pathology platforms are now poised to truly impact the future of digital toxicologic pathology, precision medicine, and personalized medicine. However, as with all great technological advances, there are implementation and adoption challenges. The development of AI and ML, application of AI in toxicologic pathology, application of ML in digital toxicologic pathology, and impact of AI on digital toxicologic pathology were reviewed in the paper, in order to provide some references for applying AI and ML in toxicologic pathology in China.
The bioequivalence studies of enteric-coated preparations are one of the difficulties in the generic drug consistency evaluation. Omeprazole is a representative drug of proton pump inhibitors (PPIs). This article summarizes and analyzes the bioequivalence studies of omeprazole enteric-coated preparations which have passed through the generic drug consistency evaluation. Some suggestions are put forward for the content, design and sample size of the bioequivalence studies, aiming to provide reference for the bioequivalence studies of omeprazole enteric-coated preparations in the future.
To explore the neuroprotective effect of acteoside (ACT) on mouse model of MPTP-induced Parkinson's disease (PD) and its mechanism.
The PD mouse model was established by intraperitoneal injection of MPTP. The experimental mice were randomly divided into control group, model group and ACT group (100 mg·kg-1), which were administrated by gavage for 14 d. After administration, behavioral evaluation and biochemical detection were performed to evaluate the neuroprotective effect of ACT on PD mice. Two-dimensional electrophoresis, mass spectrometry and Western blot were used to further explore the anti-PD mechanism of ACT.
After prophylactic administration of ACT, the pole climbing time of MPTP-induced PD mice was significantly shortened, swimming test score was improved, suspension duration was prolonged, and hind limb tension test score and cylinder test score were decreased. ACT could effectively improve the activities of SOD, CAT, and GSH-Px in the substantia nigra and striatum of MPTP-induced PD mice and reduce the content of MDA. The results of two-dimensional electrophoresis and Western blot showed that the expression of biliverdin reductase B (BLVRB) increased in the substantia nigra and striatum of PD mice induced by MPTP, while the expression of BLVRB decreased significantly after the administration of ACT.
ACT has neuroprotective effect on MPTP-induced PD mice, and its underlying mechanism may be related to the decrease of BLVRB expression and anti-oxidative stress of ACT.
Based on domestic and foreign practical experience, this article analyzes the potential effects and advantages of using cross-border e-commerce to import and use unregistered rare disease drugs, and proposes an implementation plan for using cross-border e-commerce to import and use unregistered drugs for rare diseases, including the use of drugs from patients, suggestions for the implementation path of the whole process from demand to final drug use and supervision. We also discuss the possible challenges and obstacles that may exist in the implementation of the program in the real world. Finally, we provide some policy recommendations on using cross-border e-commerce to import and use unregistered drugs for rare diseases.
Reference listed drug, as the benchmark of generic drugs, is the reference drug for the consistency evaluation of quality and efficacy of a generic drug. As the starting point of developing a generic drug, reference listed drug selection is of great significance in the whole process of research and development. This paper comprehensively reviews the policy requirements of reference listed drug selection, and compares the regulation patterns on reference listed drug in China and the United States. Moreover, the common issues on those refused reference listed drug applications are summarized, and the reasons on reference listed drug alteration are analyzed. Consequently, it is expected that the principles and approaches of reference listed drug selection would be further clarified for the reference of the applicants.
To observe the single dose toxicity and repeated dose toxicity of benvitimod, and to provide evidence for clinical administration and drug safety.
Single dose toxicity: The animals were given benvitimod 2 000 mg·kg-1 (mice) or 500 mg·kg-1 (rabbits) by subcutaneous injection. After administration, the animals were continuously observed for 14~15 days, and the toxic reaction and deaths were recorded. Repeated dose toxicity: benvitimod was administered subcutaneously to rats at doses of 40, 100, and 200 mg·kg-1·d-1 and to rabbits at doses of 30, 60, 150 mg·kg-1·d-1 for 6 months and observed for 1 month after the end of administration. The general conditions of the experimental animals were observed daily, and the body weight and food intake of the experimental animals were measured weekly. Twenty-four hours after the last administration, 50% of the animals (male and female) in each group were taken for hematology, blood biochemistry and pathology examination. The remaining animals were discontinued for 1 month, and the corresponding indexes were checked as before.
In the study of single dose toxicity, the NOAEL dose of benvitimod was 2 000 mg·kg-1 on mice and 500 mg·kg-1 on rabbit. In the study of repeated dose toxicity, after 6 months of subcutaneous injection, the NOAEL dose of benvitimod was 200 mg·kg-1 on rats and 150 mg·kg-1 on rabbit.
The results indicated that benvitimod had good safety in the clinical dosage.
Oliceridine is a G-protein-biased μ-opioid receptor agonist. It was approved by the U.S. FDA for the treatment of moderate to severe acute pain in adults by intravenous injection on August 7, 2020. Clinical studies have shown that oliceridine has a favorable analgesic efficacy which is noninferior than morphine with a lower risk of opioid-related adverse events than conventional opioids at the same time. This review focuses on the mechanism of action, pharmacokinetics, pharmacodynamics, clinical studies and safety evaluation of oliceridine．
To investigate whether β-caryophyllene (BCP) can reduce cerebral ischemia-reperfusion injury (CIR) in rats via activating heat shock factor 1 (HSF1)/heat shock protein 70 (HSP70) pathway.
Male SD rats were randomly assigned to the sham operation group, model group, BCP low, medium, and high dose groups (204,306,408 mg·kg-1), BCP (306 mg·kg-1)+Kribb11 intervention group, and Kribb11 intervention group. The suture method was used to create a rat model of CIR injury, and the neurobehavioral score was recorded 24 hours after the reperfusion. The volume of the cerebral infarct was measured using 2,3,5-triphenyltetrazolium chloride staining, and the pathological changes of cortical neurons were observed using hematoxylin-eosin staining and Nissl staining. Western blotting was applied to detect protein expressions of HSP70, HSF1, p-HSF1, Chop, Caspase 3, Bcl2, and Bax in rat brain cortex; immunofluorescence staining was used to detect protein expressions of p-HSF1 and HSP70; and Tunel staining to evaluate cell apoptosis level. Malondialdehyde level in cortical tissue (MDA), activities of total superoxide dismutase (SOD) and Caspase 3 were measured using a chemical colorimetric technique.
Compared to the model group, the β-caryophyllene administration group indicated a lower cerebral infarct volume in rats (P<0.01), a lower level of MDA and Caspase 3 activity in the tissue (P<0.01,P<0.05), a decreased expression of Bax, Chop, and Caspase 3 protein (P<0.01), a decreased occurrence of cell apoptosis, and increased protein expressions of HSF1, p-HSF1, HSP70, and Bcl 2 in the tissue (P<0.01), and substantially greater SOD activity in the tissue (P<0.01), reducing ischemia-reperfusion injury. Compared with the BCP group, Kribb11 in the BCP+Kribb11 group antagonized the curative effect of BCP, the protein expressions of HSF1, p-HSF1 and HSP70 were significantly reduced (P<0.05, P<0.01), and tissue oxidation stress levels increased, cortical cell death increased, and ischemia-reperfusion injury aggravated.
In rats, β-caryophyllene can alleviate cerebral ischemia-reperfusion injury in rats by reducing oxidative stress and minimizing cell apoptosis, which is associated with the activation of the HSF1/HSP70 pathway.
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