Malignant tumors, Alzheimer’s disease, diabetes, rheumatoid arthritis… These intractable diseases that threaten human health have long plagued us, bringing pain and suffering to unfortunate patients, and also bringing frontline researchers Pressure and challenge. It is the peak that many scientific research institutions intend to leap, and it is also a hot potato that the market covets.
For these diseases with complex mechanisms, how to build an accurate drug pharmacology model? What should a mature drug pharmacology system have? How can emerging technologies and platforms help drug development?
01 The rapid development of biotech drugs
Tumor immunotherapy is the most promising research direction in the field of tumor therapy by modulating the body’s immune system, inhibiting and killing tumor cells.
(1) PD-1/PD-L1 inhibitors continue to emerge at immune checkpoints;
(2) Cellular immune CAR-T therapy multiple products under development;
(3) Gene editing technology drives the progress of gene therapy.
02 The emergence of new anti-inflammatory and immune drugs
Autoimmune disease refers to a series of diseases caused by the body’s immune response to self-antigens, which leads to autologous tissue damage. With the deepening of research, more and more inflammatory cytokines have been discovered. Among them, JAKs (Janus kinases) have been found to be necessary signal transduction mediators for many downstream inflammatory cytokines. JAKs are a class of non-receptor tyrosine kinases, including JAK1, JAK2, TYK2 and JAK3. Ligands induce receptor aggregation to activate JAKs, and activated JAKs can phosphorylate the receptor, which in turn activates another STAT protein. JAKs and STATs are important components of many cytokine receptor systems, and an intracellular signal transduction pathway closely related to inflammatory cytokines.
In many autoimmune diseases, IL-6 interleukin is closely related to the JAK-STAT signaling pathway, and its signal transduction is mediated through the JAK/STAT pathway. Monoclonal antibodies targeting IL-6 have achieved good results in the clinical treatment of rheumatoid arthritis, confirming the importance of JAK-dependent cytokines in immune pathogenesis. A variety of JAKs small molecule inhibitors for autoimmune diseases have been developed. Based on their selectivity and different targets, they can be divided into:
(1) Non-selective JAK inhibitor;
(2) Selective JAK inhibitor;
(3) JAK and other kinase inhibitors.
JAKs inhibitors involve multiple receptors, targets and signal pathways, and are significant for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, atopic dermatitis, etc. The therapeutic effect. To this end, when evaluating the efficacy of JAKs inhibitors, we can build a variety of disease models, such as the rheumatoid model (CIA mice, rats, AIA rat models), inflammatory bowel disease models (TNBS rats , DNBS rats, DSS mice), psoriasis models (imiquimod model, IL-23 model), atopic dermatitis model (DNFB mouse chronic model, phorbol ester acute model, etc.).
Autoimmune disease animal model
The establishment of the CIA model is to administer the drug to the root of the tail of the rat, and boost the immunization after 7 days. Obvious swelling of the toes of the rat’s foot can be observed in 10-14 days. From the comparison of the above figure and the figure below, it is not difficult to find that the growth trend of the foot volume measurement is highly consistent with the growth trend of the arthritis index, which can well simulate immune arthritis.
Immune Arthritis Model
In the modeling of psoriasis model, the psoriasis-like changes in the back skin of mice induced by pyriquimod can successfully simulate psoriasis and serve as a drug effect model. It can be seen from the picture on the lower right that the typical pathogenesis of psoriasis is hyperplasia of the epidermis and hypokeratosis of the epithelial tissue. The black hair of C57 mice can be used to observe the phenotypic characteristics of psoriasis more clearly.
Psoriasis model
Interleukin IL-23 induced psoriasis-like changes in mouse auricles is another pharmacodynamic model that simulates psoriasis. This model has certain difficulties in modeling, and it is easier to fail in modeling due to inflammation. After many years of experience and knowledge accumulation, Dr. Dong has been able to approach the success rate of modeling to 100%. The picture shows the IL-23 mouse auricular psoriasis-like change model constructed by Dr. Dong, from the bottom right You can clearly see the obvious inflammatory cell infiltration and epithelial cell hyperplasia and hypokeratosis on both sides of the ear.
Psoriasis-like changes of mouse auricle induced by interleukin IL-23
In the modeling of atopic dermatitis, for chronic proliferative dermatitis, you can choose to use the DNFB model to simulate the chronic model. The model takes 28 days to build the model. Through the number of scratches, skin lesion scores, skin weight and skin thickness, The pathological examination of skin tissue and other indicators evaluate the model; for acute exudative changes, the phorbol ester model can be used to simulate the short modeling time, which can cause acute swelling of the mouse auricle.
03 The popularity of new drugs for metabolic diseases continues to rise
Due to the dietary preferences and lifestyles of modern people, a considerable part of the population is plagued by metabolic diseases, so the research and development of new drugs for metabolic diseases is also rising. Two of the most typical are non-alcoholic fatty liver and diabetes.
Non-alcoholic fatty liver disease can be divided into:
The first stage, non-alcoholic fatty liver (NAFL), can be completely reversed by diet, exercise and other healthy living. Drug treatment is mainly to improve lipid metabolism;
The second stage, non-alcoholic steatohepatitis (NASH), is a progressive form in the spectrum of non-alcoholic fatty liver disease. It is a metabolic stress liver injury closely related to insulin resistance and genetic susceptibility, which can progress to the liver. Cirrhosis and hepatocellular carcinoma are also significantly associated with an increased risk of cardiovascular disease. Drug development for NASH mainly includes FXR agonists, PPAR agonists, GLP-1 receptor agonists and drugs that act on multiple targets.
The third stage of the disease process will cause liver fibrosis, and more serious will develop into liver cirrhosis and liver cancer.
Diabetes is another chronic metabolic disease that has plagued human health for a long time. The current treatment methods are mainly controlled by drugs. Diabetes is mainly divided into type I and type II. Type I diabetes patients account for a relatively small proportion. The cause of the disease is related to autoimmunity and needs to rely on exogenous insulin for life; Type II diabetes accounts for 90% and 95% of diabetes, usually due to long-term diet Irregular habits are caused, which can be controlled by improving diet.
The research and development of diabetes drugs is divided into ultra-short-acting insulin, short-acting insulin, intermediate-acting insulin, and long-acting insulin according to the duration of drug action.
04 Medicilon drug pharmacology system
The Pharmacodynamics Department of Medicilon has rich experience and effective animal models in the evaluation of new drugs, which can meet the research and development needs of different types of new drugs of customers.
In the field of neuropsychiatric system diseases, Medicilon Pharmacodynamics Department has established covering antidepressants, anti-alzheimer’s drugs, sedative hypnotic anxiolytics, analgesics, anticonvulsants, anti-Parkinson’s drugs and antipsychotics The evaluation technology of schizophrenia drugs and many other diseases and mental system disease models can comprehensively evaluate a class of innovative drugs from multiple levels such as molecular level, cellular level, Ex-vivo, and invivo. The advanced Cognition Wall Discrimination Learning memory function tracking test system of the Department of Pharmacodynamics, 24h continuous tracking test, can effectively judge the memory function changes of Alzheimer’s double genetically modified mice that are still in the early stage of the disease, and exclude them The disadvantages of Morris water maze stress interference and short-term testing.
In the field of inflammation and immune system diseases, Medicilon’s pharmacology evaluation system includes models and evaluation methods for immune arthritis, psoriasis, atopic dermatitis, ulcerative colitis, and various acute and chronic inflammatory diseases. Especially for the recent research and development of new drugs focusing on some specific immune targets on the inflammatory pathway (such as JAK/STAT pathway, IL-23 pathway, etc.), they all have mature and stable evaluation methods, and have also tested many Chinese and foreign drugs. The innovative drugs of enterprises and research institutes have been effectively evaluated and received high praise.
In the field of metabolic diseases, Medicilon Pharmacodynamics Department has dozens of stable and effective animal models, especially for NAFLD disease, which lacks effective drug treatments in clinical practice, and has rich experience and effective animal models in the field of NAFLD diseases, including high Golden hamster and rat model induced by fat feeding, mouse model induced by MCD feed, etc. And it has effective evaluation models for NAFLD fibrosis stage, including: compound factor method induced rat liver fibrosis model (rat), ConA-induced mouse liver fibrosis (mouse), pig serum-induced immune rat liver Fibrosis model (rat), etc.
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