● 1. What is andrographolide?
Andrographolide is a diterpene lactone compound, which is the main active ingredient of clinically widely used injections. It has anti-inflammatory, anti-viral, liver-protecting, immune regulation, anti-tumor, cardiovascular disease, anti-diabetes and neuroprotection, abortion of pregnancy and other pharmacological effects.
● 2. What are the main effects of andrographolide?
Andrographolide from Andrographis panicultata (Burm. F) extracted from the whole plant Nees main active ingredient, anti-inflammatory, anti-viral, liver and gallbladder, immunomodulatory, anti-tumor, treatment of cardiovascular diseases, anti-diabetic, neuroprotection, Stop a variety of pharmacological effects such as pregnancy. Because it is a diterpene lactone compound, andrographolide is difficult to dissolve in water, and traditional Chinese medicine decoction method is difficult to precipitate, and various forms of injection have been prepared for clinical use.
2.1 Development of andrographolide
The medicinal plant, Andrographis paniculata, is a genus of genus, which has bitterness, coldness, heart, lung, large intestine and bladder. It has the effects of clearing away heat and detoxifying, cooling blood and reducing swelling. Its medicinal part is dry aerial part, and its stem is in early autumn. Pick and dry when Ye Maosheng. Studies have shown that the effective compounds isolated from Andrographis paniculata are mainly diterpene lactones and flavonoids. Modern pharmacological studies have shown that the diterpenoids represented by andrographolide are the pharmacodynamic substance basis for the pharmacological activity of Andrographis paniculata. The single component of the substance and andrographolide has been made into a variety of dosage forms (tablets, pills, capsules, etc.) and is widely used in clinical practice. The number of production approvals issued by the state has reached more than 600. However, its water solubility is poor, oral bioavailability is extremely low (less than 3%), and the taste is extremely bitter. It is easy to cause vomiting when taken orally, and the patient's compliance is poor. Therefore, the researchers used it as a basis for semi-synthesis and introduced hydrophilic groups. The group is made into a salt to make an injection, that is, Yan Hu Ning, Chuan Hu Ning and Lian Bizhi for injection. It is often used in combination with azithromycin and ribavirin for the treatment of anti-inflammatory and anti-viral related diseases.
2.2 Pharmacological effects of andrographolide
In recent years, in addition to the basic anti-inflammatory and antiviral activities of andrographolide, most researchers at home and abroad have also found that andrographolide and its derivatives also have hepatoprotective, anti-cancer, and
High immunity, anti-cardio-cerebral vascular disease, treatment of diabetes, neuroprotective effects, termination of pregnancy and other effects.
2.2.1 Anti-inflammatory effects Andrographolide and its derivatives have significant anti-inflammatory activity.
Studies have shown that the active constituents of Andrographis paniculata can inhibit the up-regulation of macrophage MMP⁃2 and MMP⁃9 activity and mRNA expression by ox⁃LDL, and thus may have the effect of maintaining atherosclerotic plaque stability and reducing the risk of plaque rupture, while Andrographis paniculata Lactone dose-dependently inhibits heart inflammation and oxidative stress, while reducing cardiomyocyte apoptosis, thereby improving myocardial fibrosis and cardiac hypertrophy. At the same time, andrographolide blocks the production of reactive oxygen species induced by hyperglycemia by inhibiting the activation of NADPH oxidase and enhancing the expression of nuclear factor erythroid ⁃ 2 related factor 2 (Nrf2) in vitro and in vivo. Andrographolide (2.5-7.5 μmol/L) can regulate the expression of HO⁃1 and GCLM in PI3K/Akt/Nrf2 and PI3K/Akt/AP⁃1 pathways of human endothelial cells, and down-regulate by inhibiting NADPH oxidase activation. TNF⁃α induces the expression of ICAM⁃1 and CD62E, which also inhibits the production of inflammatory factors such as IL⁃1, IL⁃6, IL⁃8 and IL⁃12. Andrographolide sulfonate (Lian Bizhi) can treat rat ear and foot swelling models and reduce IL⁃1 in serum. Andrographolide reduces the growth of immune organs such as thymus and spleen in a dose-dependent manner. This is related to the down-regulation of cell adaptation and humoral adaptive immune response by andrographolide, which blocks the adhesion and migration of neutrophils. The anti-inflammatory effect is closely related. At the same time, it also significantly reduced the secretion of bronchial sIgA and gamma interferon, and slowed down or attenuated lung inflammation. The structure is shown in Figure 1.
2.2.2 Antiviral effect Andrographolide is the active ingredient of Andrographis paniculata and has strong antiviral activity against EV
Antiviral effect Andrographolide is the active ingredient of Andrographis paniculata and has strong antiviral activity against EV⁃D68 infection.
Andrographolide treatment significantly inhibited EV⁃D68 RNA replication (EC50=3.45μmol/L) and protein synthesis, and did not produce significant cytotoxicity at the anti-virus concentration. The results showed that ADO was matured by virus-containing endosomes targeting EV⁃D68. Suppresses the replication of EV⁃D68. Studies have shown that 90% ethanol extract from dried leaves of Andrographis paniculata can inhibit monkey retrovirus (SRV, one of the pathogens causing acquired immunodeficiency syndrome) transfected on A549 cells, with the effect of the positive drug Lamiv Similar to the A549 cell line, the toxicity was relatively small, and compared with the control group, the low dose of Andrographis paniculata extract (1 μg/mL) stimulated lymphocyte proliferation by 38%. For the Honglin virus, respiratory syncytial virus, Ebola virus, which acts as a furin, the andrographolide can achieve antiviral effect by inhibiting the cleavage of the glycoprotein fluorescent peptide on the surface of the viral envelope. Yanhuning has the advantages of short treatment, quick effect and no adverse reactions for the treatment of hand, foot and mouth disease caused by enterovirus. In addition, andrographolide also inhibits influenza A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, human herpesvirus, human papillomavirus, chikungunya virus and other viruses.
2.2.3 Hepatoprotective effect The pre-administration of andrographolide can counteract the hepatotoxic effects caused by carbon tetrachloride, D-galactosamine and acetaminophen, and can significantly reduce the levels of SGPT, SGOT, SALP and HTG, respectively.
By injecting andrographolide into mice, it was found to be resistant to liver damage caused by carbon tetrachloride, protect the liver, and improve liver function. The hepatoprotective effect of andrographolide may be related to its inhibition of lipid peroxidation and reduction of oxygen free radical production. At the same time, andrographolide can increase the amount of bile flow, bile salts, bile acid and deoxycholic acid in experimental rats, thereby reversing the reduction of secretions such as bile caused by drugs to improve liver function.
2.2.4 Immunomodulatory effects It has been reported that andrographolide has a certain regulatory effect on cellular immunity, and exerts immunomodulatory effects through the effects on the secretion of macrophages, NK cells and cytokines.
Animal experiments have shown the establishment of an experimental autoimmune encephalomyelitis model (EAE). Compared with the control group, lymphocytes infiltrated in the central nervous system of the mouse in the EAE group. The proliferation of spleen T lymphocytes increased with the concentration of myelin oligodendrocyte glycoprotein 35-55, and CD4+ and CD25+ regulatory T cells accounted for The proportion of CD4+ T cells was significantly decreased (P<0.01), the expression of IL⁃17 and IFNγ mRNA was significantly increased (P<0.05), and the expression of Foxp3 mRNA was significantly decreased (P<0.05). Andrographolide sulfonate To increase the spleen and thymus of immunodeficient mice and improve the phagocytic ability of abdominal macrophages. By studying the effect of andrographolide on lymphocyte immune function in septic mice, it was proved by experiments that andrographolide can improve the cecum Ligation of spleen CD4+, CD8+ T lymphocytes and CD19+ B lymphocytes in spleen sepsis mice, reducing apoptosis of thymus CD3+ T lymphocytes, thereby regulating lymphocyte immune response in septic mice, but the specific mechanism remains Further research is needed.
2.2.5 Anti-tumor effects In recent years, the study on andrographolide has focused on pharmacological studies of chemical modification and its anti-tumor.
Studies have found that andrographolide and its derivatives show different levels of anti-tumor activity in many in vitro and in vivo models. Such anti-cancer mechanisms may increase lymphocyte anti-cancer activity and inhibit cell growth.
Colonization, induction of apoptosis and other aspects. The study further proved that andrographolide can inhibit the proliferation of BGC⁃823 cells, arrest its cell cycle in G0/G1 phase and induce its apoptosis, showing strong anticancer effect, and is a potential anticancer drug preparation for gastric cancer. ingredient. The anticancer activity of andrographolide and its derivatives was tested. A series of andrographolide analogues were prepared by chemoselective function of C⁃14 hydroxyl group, against human leukemia cells, andrographolide in vitro. Shows certain anticancer toxicity. Experiments show that andrographolide and its derivatives all show strong anticancer activity. A preliminary study on the structure-activity relationship found that andrographolide α-methine-γ-butyrolactone played an important role in the activity spectrum. The structure of the analog was established by spectroscopy and data analysis. Since the hydroxyl group at position C⁃14 has a selective function, the C⁃14 position was selected. The conversion of andrographolide and its derivatives to the appropriate derivative ester (C⁃14) can greatly increase its solubility and activity. After esterase cleavage of the ester bond, the andrographolide can be released under physiological conditions in vivo. As a prodrug. Based on this purpose, an andrographolide derivative modified at position C⁃14 was synthesized. Studies on the structure-activity relationship (SAR) of derivatives have shown that the main function is the α-methine-γ-butyrolactone group.
2.2.6 Treatment of Cardiovascular Disease The active constituents of Andrographis paniculata are flavonoids and lactones. Flavonoids prolong thrombus formation and inhibit platelet aggregation in cardio-cerebral vascular diseases, scavenging free radicals and anti-lipids.
It has anti-atherosclerotic effects such as peroxidative damage. Lactones have antihypertensive and lipid-lowering effects, anti-ischemic and ischemia-reperfusion injury effects, anti-atherosclerosis, prevention of restenosis after angioplasty, and improvement of blood rheology. Chan et al used a permanent rat middle cerebral artery occlusion (pMCAO) rat model to investigate the potential therapeutic effects of andrographolide on cerebral ischemia. It was found that 1 hour after intraperitoneal injection of pMCAO, the neurological deficit was reduced, reflecting the correlation between infarct volume and neurological dysfunction. Studies have found that improving the body's antioxidant capacity is one of the mechanisms of andrographolide against cerebral ischemia-reperfusion injury. In addition, andrographolide can prevent the decrease of Na+⁃K+⁃ATPase and Ca2+⁃ATPase activity during cerebral ischemia-reperfusion, which affects the formation of intracellular calcium overload and reduces brain tissue damage to varying degrees. Feng Yuli et al found that the antiplatelet effect of andrographolide was correlated with the drug dose. The thrombus formation time of rats was significantly prolonged after taking andrographolide.
2.2.7 Anti-diabetic effect It was found that andrographolide and its derivatives acted as a hypoglycemic agent in diabetic mice, and increased superoxide dismutase in serum and pancreatic tissue.
Activity, reduced malondialdehyde content, improved insulin resistance in mice.The mechanism may be related to inhibition of islet cell apoptosis and up-regulation of gene expression levels. In vitro experiments have shown that the inhibitory effect of andrographolide and lipoic acid dehydration condensation derivative AL⁃1 on α-glucosidase.
2.2.8 Neuroprotective effects
It has been found that andrographolide has neuroprotective effects on glutamate-induced oxidative stress model of HT22. Andrographolide can reduce early apoptosis of HT22 cells by inhibiting the influx of calcium ions into cells and intracellular oxidation, not only that, but It also controls the expression of apoptotic factors such as Bcl⁃2, Bid and Bax.
2.2.9 Stopping Pregnancy The effect of Andrographis paniculata has a significant effect on the termination of pregnancy.
It inhibits the secretion of hormones from the early pregnant human placental villus trophoblast cells and damages the trophoblast cells to death.The role of Andrographis paniculata has multiple routes of administration to terminate pregnancy.
● 3. Adverse reactions of andrographolide
The andrographolide structural modification products are inferior to the parent compound in chemical stability and safety effectiveness. In clinical use, there are often certain allergic reactions and toxic side effects, such as damage to the skin and its attachments, systemic damage, circulatory damage, Respiratory damage, digestive system damage, blood system damage, kidney damage, nervous system damage, etc. After taking the drug, the number of patients with adverse drug reactions occurring within 15 minutes accounted for 50% of the total number of patients, and the number of patients with adverse reactions occurring during 15 to 30 minutes accounted for 21% of the total number of patients. The adverse reactions occurred in patients with more than 30 minutes. The number of patients accounted for 29% of the total number of patients. In the case of adverse reactions, 88% of the total number of patients required to use anti-allergic drugs or hormones in addition to the temporary use of adverse drug reactions. Thus, although andrographolide plays an important role in the clinical treatment of viral pneumonia and viral upper respiratory tract infection, it can also cause systemic damage, skin mucosal damage, respiratory damage, digestive system damage. , cardiovascular system damage, nervous system damage and other major adverse reactions, but the cause of adverse reactions is still not very clear, so it is necessary to investigate its stability, to explore the possible substances involved, and conduct relevant toxicity tests In addition, Yanhuning for injection is often used in combination with azithromycin, erythromycin, and cefmenoxime in clinical practice. Therefore, the study of drug habits and clinical incompatibility studies is also an important guarantee to avoid side effects and improve drug safety. The clarification of its application security issues will also play a necessary supporting role.
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