ArchiveAchievements have been made in the development of pharmaceutical innovation in China since the Chinese Communist Party's 18th National Congress. China is moving toward from follow-on innovation to the original innovation. This paper reviews current situation of the drug innovation, analyzes the existing problems and obstacles, and puts forward corresponding suggestions. New challenges for the future of pharmaceutical innovation include lower innovative capability, risk of dependence on foreign technological in some key chains, lack of top pharmaceutical companies in the world, etc. Several suggestions for resolving these capital, talent, technology, system, and policy problems are proposed as follows: taking advantage of the new system for mobilizing resources nationwide, improving the efficiency of innovation investment, coordination of talent attraction policies and science and technology policies, developing industry-university-institute-hospital R&D, perfecting related policy and ecosystem environment.
In recent years, with the aging of the global population and the general improvement of consumer awareness, disease prevention and early intervention have been paid more and more attention, and the traditional Chinese medicine (TCM) industry, which has the unique advantage of "preventive treatment of disease", has ushered in a huge development opportunity. Especially under the special background of the global COVID-19 pandemic, TCM has played an important role and provided a good opportunity for its industrial development. With the promulgation of a series of policies in China, the inheritance and innovative development of TCM have been accelerated. In this paper, we investigated the TCM's domestic and foreign market, research and development investment of enterprises, approval trend of innovative drugs, and internationalization and the layout of patents in the past 20 years, analyzed the current situation of TCM innovation and development, and looked forward to the future trend, with a view to provide inspiration for the future inheritance and innovation of TCM.
To understand the innovation points of drugs marketed after the implementation of the U.S. breakthrough therapy designation (BTD) program, and provide a reference basis for the development of innovative drugs and the review of breakthrough therapy drugs in China.
As of 2021, all BTD drugs approved by the U.S. FDA for marketing were collected, and the characteristics of these drugs in terms of innovative therapeutic modalities, treatment mechanisms, and technological breakthroughs were categorized and statistically analyzed.
The US FDA received 1 192 BTD drug applications and approved 242 for marketing. Among the marketed drugs, 42 (17%) were new drugs to fill clinical treatment gaps, 99 (41%) were drugs for expanded indications and new applicable populations, 27 (21%) were drug combinations for combination therapy, 16 (7%) were new drugs with more clinical treatment advantages, 31 (12.8%) were drugs with new mechanisms of action, and 12 (5%) were drugs prepared in new dosage forms or processes.
The substantial improvement of the clinical efficacy of BTD drugs is reflected in the innovation of drugs and advancement of treatment.
Zynteglo (betibeglogene autotemcel) is the world's first gene therapy approved by the U.S. Food and Drug Administration on August 17, 2022 for adults and children with β-thalassemia who require regular blood transfusions. Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient's own $\mathrm{CD}_{34}^{+}$ bone marrow hematopoietic stem cells which are genetically modified in vitro and then autologously transplanted. The modified stem cells will differentiate into red blood cells which are capable of producing functional hemoglobin, therefore achieving the purpose of β-thalassemia treatment. This paper provides a comprehensive introduction to the gene therapy from six aspects: lentiviral vector and mechanism of action, non-clinical research, clinical efficacy research, clinical safety research, indications and methods of use, and precautions.
Roflumilast is a selective phosphodiesterase-4 inhibitor. Roflumilast 0.3% cream was approved by the U.S. FDA on July 29, 2022 (trade name Zoryve) for the treatment of plaque psoriasis in patients of 12 years or older, including intertriginous areas. Unlike other topical medicines, roflumilast has a higher safety profile, it is non-irritating to the skin, can be used continuously in long-term, and does not thin the skin. This article reviews its mechanism of action, pharmacokinetics, safety, clinical efficacy and precautions for use.
The U.S. Food and Drug Administration (FDA) has issued a series of policy documents in recent years to accelerate the approval and marketing of generic drugs. This article briefly introduced the relevant contents of one of these documents, i.e., "Good Abbreviated New Drug Application Assessment Practices", to explain how the US FDA tries to find a way, from the agency's perspective, to standardize the review process of generic drugs, and improve the review efficiency and effectiveness to promote generic drug marketing without quality compromising. Also, some thoughts were put forward respecting the relevant policies for the reform of China's drug review and approval system.
Non-alcoholic steatohepatitis (NASH) has a global prevalnce of about 3%~5%, and lifestyle interventions are the main prevention and treatment methods of NASH. The diet pill orlistat, antioxidant vitamin E, and insulin sensitizer pioglitazone have certain therapeutic effects on NASH. In recent years, many therapeutic drugs for NASH of different mechanisms have entered clinical trials at different stages, such as the double agonist lanifibranor of peroxisome proliferator activated receptor α/δ, glucagon-like peptide-1 receptor agonist liraglutide, acetyl CoA carboxylase inhibitor firsocostat, thyroid hormone receptor agonist resmetirom, stearyl-CoA desaturase-1 inhibitor aramchol, sodium-glucose cotransporter 2 inhibitor dapagliflozin, fibroblast growth factor-21 analogue efruxifermin, Fani-X receptor agonist obeticholic acid, etc. In this paper, the current status of NASH treatment and clinical research of new drugs are systematically summarized.
To study the distribution of expanded activated lymphocytes in severe immunodeficient mice.
Ninety-six NPG mice were used and randomly divided into vehicle control group and administration group. The animals in the vehicle control group were given vehicle by tail vein injection once; the animals in the administration group were given DiR-labeled EAL cells by tail vein injection once. Blood was collected at different time points after administration, and EAL cells were detected by in vivo imaging system. At 1 h, 3 h, 2 d, 7 d, 14 d, 28 d, 42 d, and 56 d after administration, the mice were anesthetized, and blood, heart, liver, spleen, lung, kidney, brain, testis, epididymis, uterus, ovary, stomach, duodenum, colon, bone marrow, fat, and skeletal muscle were taken for cryopreservation. The distribution of EAL cells in peripheral blood and the above-mentioned tissues was studied by flow cytometry, in vivo imaging method and qPCR method.
The numbers of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells in peripheral blood were higher at 2 d after administration, and then showed a downward trend, reaching the lowest at 14 d, and maintained a low level thereafter. The results of in vivo imaging showed that the cells were mainly distributed in the lungs, liver, spleen and bilateral leg bones, and were mainly distributed in the lungs and liver within 1 d after administration. The results of gene copy number detection showed that the cells were mainly distributed in the lungs and blood, followed by the spleen, liver and bone marrow, and only a little in other tissues. At 1 h after administration, the gene copy number of cells in the lungs was relatively high. At 2 d, the number of gene copies in the blood and spleen was relatively high, and then gradually decreased, reaching the lowest at 14 d, and at 56 d cells were only detected in individual organs of one mice.
EAL cells were administered to NPG mice, the cells were mainly distributed in lung, blood and spleen. At 56d after administration, the cells were basically eliminated from the mice.
Ergosterol peroxide, a derivative of ergosterol, is widely found in a variety of medicinal fungi and plants and has various biological activities because of its 5α, 8α-peroxide bridge structure, such as anti-tumor, anti-virus, immune regulation, bacteriostasis and anti-inflammation. It is worth noting that the anti-tumor activity of ergosterol peroxide is significantly higher than ergosterol. At present, the preparation processes of ergosterol peroxide mainly include biological extraction and chemical synthesis. Biological extraction fails to acquire a large amount of ergosterol peroxide because of its low content in natural resources. However, chemical synthesis is convenient, and may realizes the industrialization of ergosterol peroxide. Here, the progress in study on biological activities and preparation of ergosterol peroxide was reviewed to provide direction for its application.
Nanocrystals possess the merits of high solubility, fast dissolution rate and high bioavailability with extremely small particle size, so they have been used in various formulations for oral, injectable, transdermal or mucosal delivery. Although injectable drug delivery is relatively reliable, the transport process of nanocrystals after injection is more complicated than that of solution. Based on literature research, this paper reviews the mechanisms of absorption, distribution, metabolism and excretion of injectable nanocrystals. Meanwhile, it also describes the factors affecting their processes in vivo, including the influence of physiological factors such as injection site, mononuclear phagocyte system, and formulation factors such as drug particle size and stabilizer. All of these provide a good foundation for further extensive application.
Ionic liquids (ILs) are a class of salts that appear liquid form at or near room temperature. They are widely used in biomedicine, especially in transdermal drug delivery, because of their simple preparation process, high stability, good solubility and flexible structure. ILs can improve drug solubility, promote transdermal penetration, improve the efficacy of drugs, and solve the problems existing in the transdermal drug delivery. This article reviewed the classification, synthesis methods and its application in transdermal drug delivery. The IL-based transdermal preparation was also summarized, in order to provide reference for further research and development of ILs in transdermal drug delivery.
Targeted protein degradation (TPD) strategies have been used by academia and industry as one of the promising new drug development technologies to address targeted proteins that are not effectively acted upon by conventional small molecule inhibitors. Protein hydrolysis-targeted chimeras (PROTAC) have become the most well-studied protein-targeted degradation technique in TPD, which comprises of a POI-binding ligand, an E3 ligand, and a linker connecting the two ligands. Once the POI ligand binds to the receptor protein, PROTAC recruits the E3 ligand to ubiquitinate the protein and finally degrades it through the ubiquitin-proteasome system. PROTAC technology offers great potential for therapeutic applications because it can target proteins that lack well-defined active degradation sites, which are often involved in the pathogenesis of cancer and other diseases. To enhance PROTAC's target delivery and tissue selectivity, the industry has begun to investigate new strategies, such as discovering new E3 ligases and developing corresponding ligands, along with continuing to investigate more emerging PROTAC modalities to further promote PROTAC. These strategies and relevant studies are discussed in this review.
To evaluate the clinical safety and effectiveness of Jiuwei Zhike mixture in the treatment of wind-heat cough syndrome of acute bronchitis.
A randomized, double-blind, double-simulation, placebo and positive drug controlled, multi-center clinical trial design was adopted. The selected disease was acute bronchitis (wind-heat cough syndrome). Seven hundred subjects from 10 research centers were planned to be included and divided into treatment group, positive drug control group and placebo group in a ratio of 3∶1∶1. The patients took Jiuwei Zhike mixture+Jizhi syrup simulation agent, Jiuwei Zhike mixture simulation agent+Jizhi syrup, or Jiuwei Zhike mixture simulation agent+Jizhi syrup simulation agent for 7 d.
Jiuwei Zhike mixture took effect on acute bronchitis (wind-heat cough syndrome) from the 3rd day of administration. By the 7th day of administration, 54.7% of the subjects' cough symptoms completely disappeared (49.2% in the positive drug group and 15.1% in the placebo group), with a clinical recovery rate of about 51.6% (43.5% in the positive drug group and 13.7% in the placebo group), and a total effective rate of 93.4% (87.1% in the positive drug group and 41.9% in the placebo group). And it had a significant improvement effect on the symptoms of the disease.
Jiuwei Zhike mixture is safe and effective in treating acute bronchitis (wind-heat cough syndrome) and its curative effect is not inferior to Jizhi syrup and superior to placebo.
To optimize the water extraction process of modified Tabusen-2 by response surface methodology (Box-Behnken) and investigate its in vitro efficacy.
Taking the mass fractions of caffeic acid and geniposide as the comprehensive score, response surface methodology was used to optimize the soaking time, material-to-liquid ratio, extraction time and extraction times. The RAW 264.7 cells induced by nuclear factor-κB receptor activator ligand (RANKL) were co-cultured with the optimal extracts for 5 d, and then treated with tartrate-resistant acid phosphatase (TRAP). The TRAP-positive cells were stained and observed under a microscope to evaluate the in vitro efficacy of the extract.
The extraction time, soaking time, and material-to-liquid ratio were selected as the inspection factors, and the comprehensive score of caffeic acid and geniposide content was used as the evaluation index. After optimization by response surface method, the optimal extraction condition was 540 min; the liquid ratio was 1∶12 (g·mL-1); the extraction time was 44 min, and the extraction times were two times. The extract obtained under this condition had a significant inhibitory effect on RAW264.7 cells induced by RANKL, could reduce TRAP-positive cells, and inhibited multinucleation.
The water extraction process of modified Tabusen-2 optimized by response surface analysis method is reproducible, stable and feasible, and has good in vitro pharmacodynamic activity, laying a reliable foundation for future in vivo pharmacodynamic experimental research.
To optimize the preparation and solidification process of paeonol nanosuspensions.
Paeonol nanosuspensions was prepared by solvate-non-solvent precipitation method. With the appearance character, particle size and polymer dispersity index (PDI) as the evaluation indexes, the type of stabilizer, stirring time, stirring speed, drug-auxiliary ratio, organic phase-water ratio and water phase temperature as the influencing factors, the preparation process of nanosuspensions was optimized, and the stability of the prepared nanosuspensions was investigated. The freeze-drying method was used for solidification, and the effect of freeze-drying protectant on solidification was investigated. The drug loading, scanning electron microscopy, differential scanning calorimetry, X-ray diffraction and dissolution in vitro of the solidified nanosuspensions were characterized.
The preparation process of paeonol nanosuspensions was povidone K60 as stabilizer, drug-to-auxiliary ratio 1∶3, organic phase water ratio 1∶10, at 25 ℃, 400 r·min-1 magnetic stirring for 30 min. The prepared nanosuspensions had a particle size of about 40 nm, with narrow distribution and good stability. The lyophilized protectant was determined to be 5% trehalose. The drug loading capacity of solidified nanosuspensions was 21.63%, and the microscopic surface morphology was spherical, and the drug structure changed from crystalline form to amorphous form. The cumulative dissolution rate of the suspension reached 87.12% in 1 h.
The formulation and preparation process of paeonol nanosuspensions are simple, easy to operate, with good formability after solidification and fast dissolution, which lay a foundation for the development of more dosage forms.
To explore the effect and mechanism of compound cortex phellodendri fluid in bacterial vaginosis rats via TLR4/NF-κB pathway.
Fifty-five SD female rats were selected to construct bacterial vaginosis model by injection of mixed bacterial liquid. After successful modeling, the rats were treated with compound cortex phellodendri fluid, metronidazole vaginal gel, and Honghe fujie lotion, respectively. After 7 d of continuous treatment, inflammatory cell infiltration and glycogen accumulation in rat vaginal tissues were observed by HE staining. ELISA method was used to detect the expression level of IL-1β, IL-2, IL-10, IL-6, and TNF-α in the vaginal lavage. The distribution of NF-κB p65 in rat vaginal tissues were located by immunohistochemical method. And the protein expression level of TLR4 and NF-κB p65 were detected by Western blot.
Compared with those of the model group, the infiltration of inflammatory cells in compound cortex phellodendri fluid group was reduced, and the accumulation of glycogen was significantly increased (P<0.01), the concentrations of IL-1β (P<0.01), IL-6 (P<0.05), IL-2, and TNF-α in the vaginal lavage were decreased, while the IL-10 concentration increased (P>0.05), the protein expression level of TLR4 and NF-κB p65 decreased (P<0.05), and the NF-κB p65's translocated nuclear were suppressed (P<0.01).
Compound cortex phellodendri fluid has a definite therapeutic effect on bacterial vaginosis rats. Its mechanism may be related to the inhibition of TLR4/NF-κB pathway and adjustion of immune imbalance on Th1/Th2.
This article reviewed the reports of adverse reactions of 17 weight-loss drugs approved by the FDA since 1887 during the clinical trials and after their marketing, including six that are still on the market and 11 that have been withdrawn due to valvular heart disease, suicidal tendencies, cancer risk, or other reasons. Weight-loss drugs can reduce weight and bring metabolic benefits in obese patients, but also cause various side effects, including psychonervous system adverse reactions, cancer risk, cardiotoxicity, liver damage, pancreatic toxicity, renal toxicity, digestive tract side effects, etc. Drugs with severe side effects will receive a black box warning from the FDA, and drugs with fatal side effects will be ordered to withdraw from the market. In addition to summarizing the side effects of weight-loss drugs, this article put forward some in-depth considerations on their safety, in order to provide reference for pharmaceutical companies to develop weight-loss drugs, clinicians and patients to use weight-loss drugs correctly and protect people's lives and health.
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