One bacterium: in vitro experiments show that Coptis chinensis or berberine has strong antibacterial effect on hemolytic streptococcus, meningococcus, pneumococcus, Vibrio cholerae, Bacillus anthracis and Staphylococcus aureus; It can inhibit Shigella dysenteriae, diphtheria, Bacillus subtilis and Streptococcus viridis. It is also effective for pneumonia, whooping cough, Yersinia pestis, Brucella, tetanus, Clostridium perfringens and tuberculosis. It has poor effect on Proteus, Escherichia coli and typhoid Bacillus, but has little effect on Shigella sonnei, Paratyphoid Bacillus and Pseudomonas aeruginosa. Due to the different experimental methods, there are some differences among the reports. For Shigella, Shigella Shultz is the most sensitive, followed by Freund's and Thorne's. Its function is equivalent to or better than sulfanilamide, but weaker than streptomycin and chloramphenicol. The antibacterial effect of crude extract of Coptis chinensis is basically the same as that of pure berberine. However, in a few cases, the effect on some bacteria is not completely consistent. The decoction has good antibacterial effect, and berberine still has antibacterial effect after being resistant to streptomycin, chloramphenicol and oxytetracycline. It has also been reported that adding berberine can restore the sensitivity of intestinal bacteria to the above drugs. In vitro and in vivo tests, it also showed synergistic effect with streptomycin and sulfanilamide on staphylococcus. Although there are many strains of berberine and sulfonamides resistant to Shigella dysenteriae at the same time, they are not completely cross-resistant. It has obvious bacteriostatic effect on Bordetella pertussis in vitro. Although its minimum effective concentration is higher than streptomycin and chloramphenicol, its clinical efficacy is at least not lower than streptomycin and chloramphenicol. It has antibacterial effect on diphtheria Bacillus in vitro; However, oral administration of Coptis chinensis can not protect the lethal effect of diphtheria Bacillus on guinea pigs, nor can it alleviate or inhibit the occurrence of local reactions and local reactions caused by intradermal injection of diphtheria toxin. It can inhibit tuberculosis in poultry, cattle and human. Due to the different culture medium and strain conditions, its inhibitory effect is obvious and not obvious, which is generally far less than that of p-aminosalicylic acid. In vivo test, the curative effect on mice, rabbits and guinea pigs inoculated with Mycobacterium tuberculosis is not very significant. It is reported that 1: 2000 berberine has no effect on the pathogenicity of bacteria to guinea pigs after three days in vitro. If 14 days later, its pathogenicity can be reduced 1/2. Other microorganisms and protozoa: In the chicken embryo test, Coptis chinensis has certain inhibitory effect on various influenza viruses and Xincheng viruses. It has a broad and significant inhibitory effect on more than ten common pathogenic fungi in test tubes. It has a strong killing effect on leptospira in test tubes, with Berberine 7.5 μ g/ml and Huanglian Decoction 1.9 mg/ml, with significant effects. Rhizoma Coptidis decoction and berberine sulfate have anti-amoeba effects in vitro and in vivo. In vitro experiments, their effects are equivalent to1128 in ipecac and 1/4 in tetrandrine. In vivo test is equivalent to116 of tetrandrine. In addition, it also has the function of resisting trichomonas, Leishmania, trypanosoma and paramecium. Because of its extensive functions, some people think that it can be used as a preservative, and its phenol coefficient is between 5 and 20. The effective antibacterial component of Rhizoma Coptidis is generally considered to be berberine. After frying Rhizoma Coptidis, the content of berberine decreased and the antibacterial activity weakened. Its low concentration (about 10 mg/100 ml) is antibacterial and its high concentration (about 20 mg/100 ml) is bactericidal. Its sterilization principle is complex and has not been fully clarified. Berberine can inhibit the growth and respiration of Staphylococcus aureus, and inhibit the oxidation process of glucose and glucose metabolic intermediates, especially dehydrogenation. It has obvious antagonism with vitamins PP and B; When it is alkaline, it can inhibit the combination of enzyme proteins of Escherichia coli and Streptococcus faecalis with pyridoxal, but it can't when it is acidic, and it can inhibit the synthesis of protein by bacteria. Coptis chinensis and its compound preparation can reduce the titer of staphylococcus aureus hemolysin and plasma protein coagulase. In the study of Vibrio cholerae, it is proved that berberine may damage the cell membrane and lead to the change of intracellular components; It does not affect the synthesis of nucleic acid, but increases the decomposition process of protein and changes the composition of fatty acids (saturated and unsaturated). It is reported that it can enhance the phagocytic function of white blood cells and hepatic reticuloendothelial system; It can make animals recover from the metabolic disorder caused by infection, such as the decrease of myocardial glycogen and some enzyme activities. Berberine (alone or in combination with phosphoramide) slightly inhibited the immune response of guinea pigs to live Brucella vaccine in the early stage, but had no effect in the later stage. Staphylococcus aureus, hemolytic streptococcus and Shigella flexneri are easy to be resistant to berberine alone. Some bacteria can also assimilate berberine from the culture medium; But there was no cross-resistance to penicillin, streptomycin, chlortetracycline, isoniazid and p-aminosalicylic acid. It is reported that the formation of drug resistance is much smaller than that of coptis chinensis alone, and the antibacterial effect is improved.
② Influence on circulatory system
Intravenous injection or oral administration of berberine can lower the blood pressure of anesthetized (dogs, cats and rabbits) or anesthetized (rats) animals. General dose, short duration, repeated administration, no enhancement and tolerance. The hypotensive effect has nothing to do with the heart, because it can excite the heart and increase coronary blood flow in general or small doses, and inhibit the heart in large doses; Even if the dose is increased, the isolated toad or cat heart will not have cardiac arrest. Lowering blood pressure is related to vasodilation, because while lowering blood pressure, the volumes of spleen, intestine, kidney and limbs are all increasing. Bufo vascular perfusion and rabbit kidney perfusion also prove that it can directly dilate blood vessels. The antihypertensive effect of berberine hydrochloride was not affected by diphenhydramine and reserpine. Atropine can block its hypotensive effect (anesthetized rats), but it does not affect the hypotensive reaction of acetylcholine; Therefore, its effect may be to directly excite muscarinic receptors. After a lot of research on various factors in the principle of blood pressure reduction, it is generally believed that its blood pressure reduction is due to the direct effect on blood vessels and the enhancement of acetylcholine (see the next section). Some principles have not been satisfactorily explained so far. For example, ergotoxine can reverse the hypotensive effect of berberine into pressor effect; Whether the pressor effect of acetylcholine can be reversed to hypotensive effect by berberine after injecting a large amount of atropine needs further study.
③ Effect on acetylcholine, etc.
Berberine can enhance the effect of acetylcholine in mammalian heart samples (heart and lung device, isolated cat heart, isolated rabbit ear and isolated cat ear), but it can be counteracted in large doses, which is also true in the whole animal. Low dose can enhance the blood pressure drop caused by acetylcholine or electric stimulation of the peripheral end of vagus nerve, while high dose can weaken this reaction. Berberine can enhance the effect of acetylcholine on rabbit ears, frog lower limb perfusion, isolated rabbit intestine and bronchus. It can also enhance the saliva secretion caused by electrical stimulation of chorda tympani nerve and pilocarpine injection. Local administration of berberine (0.5%) can enhance the effect of acetylcholine in rabbit pupil experiment. In addition, it can significantly enhance the effect of acetylcholine on rectus abdominis, showing significant antitoxic effect in small doses and enhancing the antitoxic effect of some drugs in large doses. The effect of antitoxin can also be observed in the whole animal body, but in the body, the effect occurs slowly, which is different from physostigmine. Its action intensity (toxicity test in rabbits and mice) is not as good as physostigmine, and its derivatives can have stronger antitoxic effect. In a word, berberine has biphasic effect; Its enhancement of acetylcholine is related to its anticholinesterase activity. Its anticholinesterase activity was determined in dog, horse serum and rabbit brain homogenate, but its efficacy was only 1/200 of neostigmine. On the other hand, the antagonism of berberine to acetylcholine may be due to the competitive antagonism between berberine and acetylcholine, and its chemical structure belongs to quaternary ammonium compounds.
Berberine also has some anti-adrenaline-like effects. In the process of lowering blood pressure caused by berberine in anesthetized animals, the pressor response of adrenaline was greatly weakened, but it recovered quickly. Berberine can antagonize arrhythmia, bradycardia and ECG changes in anesthetized rabbits caused by adrenaline and its analogues such as norepinephrine, isoproterenol and methoxyamine.
④ Effect on smooth muscle
Berberine not only relaxes vascular smooth muscle, but also excites other smooth muscles such as uterus, bladder, bronchus and gastrointestinal tract. In vitro, it has a significant stimulating effect on the uterus of guinea pigs and cats, even surpassing Berberine in North America, which is meaningful in obstetrics and gynecology. Low concentration of Rhizoma Coptidis decoction can increase the tension of isolated rabbit intestine, while high concentration can cause relaxation.
⑤ Effect on bile secretion and blood.
Berberine is beneficial to gallbladder function, increases bile production and makes bile thinner. Oral administration has a good effect on patients with chronic cholecystitis. In chronic experiments, berberine can reduce serum cholesterol by oral administration (20 mg/kg) and intramuscular injection (2 mg/kg) in rats. After feeding cholesterol or thyroidectomy, the hot water extract of Coptis chinensis can make the increased serum C/P value return to normal earlier or reduce the blood lipid level. Sanhuang powder (Rhizoma Coptidis, Scutellariae Radix and Radix et Rhizoma Rhei) can reduce the increased c/P value for phenylhydrazine arteriosclerosis in rabbits. The hypoglycemic effect reported in early years has not been confirmed. It is reported that berberine and some bitter stomach-invigorating drugs (caryophyllene in clove, etc. ) has anti-anemia effect. In rabbits with anemia caused by injection of phenylhydrazine and diaminotoluene, berberine has a lower effect on red blood cells than the control group, but has a higher effect on hemoglobin to a certain extent. However, there are also reports that coptis powder has not been found to have this effect. Berberine, which was reported in early years, can reduce white blood cells and inhibit amoeba-like movement of white blood cells. It has not been confirmed, but it has no effect on white blood cells at ordinary doses.
⑥ Anti-cancer, anti-radiation and their effects on cell metabolism.
Berberine was once considered as protoplasmic toxin or cytolytic toxin. It belongs to stilamin compounds with colchicine and chelidonine, and has synergistic effect with colchicine. In tissue culture test, it inhibits cell respiration and oxygen uptake, causing cell steatosis. Fluorescence photography showed that berberine existed in intracellular granules. Its inhibitory effect on cell respiration is mainly due to its inhibitory effect on oxidative decarboxylation of pyruvate, but it has no effect on isobutene diacid, fumaric acid, acetic acid and anaerobic glycolysis. Some people think that its respiratory inhibition is mainly due to the inhibition of xanthase, and the content of xanthase in cancer tissue is low, so it is more sensitive to berberine than normal cells. It is also reported that it can inhibit the nucleic acid synthesis of cancer cells and the utilization of carboxyl amine, an intermediate of purine nucleotide synthesis. Although it has anticancer effect in vitro, it has poor therapeutic effect on Ehrlich ascites cancer in mice. Berberine has a certain protective effect on the death of mice irradiated by Coγ -rays According to yeast experiments in vitro, this protective effect may be related to berberine changing some characteristics of the surface of intracellular microsomes.
All landowners other functions
Low dose berberine can enhance the excitement process of cerebral cortex in mice, while high dose can weaken this process. At the same time, it can also strengthen the inhibition process. Berberine can stimulate chemoreceptors in carotid body, bone marrow and intestine. Carotid injection is different from intravenous injection of this drug, it will not cause sustained hypotension, but will cause fluctuations in blood pressure. This phenomenon may be related to its reflex pressor effect on carotid body. In the experiment of croton oil granulation sac in rats, it was proved by histological method that subcutaneous injection of berberine could help the body to strengthen the barrier to inflammatory lesions. The methanol extract of Coptis chinensis has anti-inflammatory effects (edema of foot and ankle in rats, croton oil granulomatous bursitis, etc.). ), local administration can also reduce the weight of granuloma, similar to butazone. It is said that berberine has antipyretic, diuretic, local anesthesia, sedation, analgesia, prolonging pentobarbital sleep time and reducing intraocular pressure in rabbits, and has no estrogen-like effect. Coptis chinensis and daylily root can be taken at the same time or in a short time, which can reduce the toxicity of the latter to mice.
8 absorption, distribution and excretion
Berberine is not easily absorbed by oral administration. Parenteral administration, absorbed into the blood, quickly into the tissue, blood drug concentration is not easy to maintain; After oral administration of 0.4 g berberine hydrochloride for 30 minutes, the plasma concentration was 100 μ g% (the bactericidal concentration in vitro was about 20 mg%), and then gradually decreased. Even after repeated administration, the blood concentration of 0.4 g every 4 hours did not increase. In vivo, berberine is distributed in almost all tissues, with heart, kidney, lung and liver being the most. Its storage time in various tissues is very short. After 24 hours, only a small amount of it is mainly metabolized in the body, and a small part (6.4%) is excreted by the kidney. Rabbits can also absorb it after oral administration, stay in the blood for 72 hours, and excrete it with urine. The heart concentration is the highest, followed by pancreas and liver. Mice take it orally, and the absorption is very small. When administered by injection, it mainly enters the heart, pancreas, liver and omentum fat; A considerable amount of berberine can still be found in pancreas and fat after 24 hours. Only a small amount (1%) is excreted from urine.