CN1771944A - Application of high-solubility berberine in preparing medicine - Google Patents

Abstract

The present invention relates to the new use of high solubility berberine in preparing medicine. The high solubility berberine may be dissolved in 500 times of water and is easy to be absorbed by human body to make best use and raise curative effect. It may be used in treating and preventing hypertension, hyperlipemia, arrhythmia, heart disease, hepatitis, etc.

Description

The application of high-dissolvability berberine in pharmacy

Technical field

The present invention relates to the new purposes of high-dissolvability berberine in pharmacy.

Background technology

From last century the fifties, some experts and scholars and medical worker have carried out a large amount of zooperies and clinical testing to the Halomine of clinically extensive use, propose berberine and also can treat diabetes and complication thereof except antibiotic, in addition, also can treat some heart, the cranial vascular diseases (seeing Table 1) such as cancer and hypertension. Though they are to effect abundant affirmation, the high evaluation of the above-mentioned disease of Berberine in treating, because the solubility of Halomine is very low, cause curative effect not bery desirable, fail to be promoted application.

Berberine another name jamaicin is morphinane alkaloid, is the effective constituent that mainly contains of the plants such as the coptis, golden cypress, radix berberidis, nandina. The TA that obtains from traditional Chinese medicine extraction such as the coptiss mainly contains Berberine hydrochloride (Halomine), citric acid jamaicin (citric acid berberine), Berberine bisulfate (Berberine bisulfate), berberine sulfate (berberine sulphate) and phosphoric acid jamaicin (phosphoric acid berberine) through further separating the monomer jamaicin that obtains from the salt that different acid form. Also can obtain various jamaicins by chemical synthesis.

The aspects such as the pharmacology of various jamaicins, toxicity, effect, side effect and purposes are identical, and different mainly is its solubility and widely different (seeing Table 2). One one, two ones of the Pharmacopoeias of the People's Republic of China are all pointed out in " note on the use ": " solubility is a kind of physical property of medicine, can reflect to a certain extent the purity of medicine. " send according to Deng and to write articles: " effective ingredient of some medicinal material is insoluble in water or water insoluble, also may dissolve a bit because of the phenomenon of dissolving each other, but some effective ingredient has wasted after all. " (Chinese medicine system is recorded with experience, China Traditional Chinese Medicine Publishing House, 1992,64～65. ) international new drug research person pays much attention to the important function of biopharmacy categorizing system (BCS) in the medicament research and development process in recent years. BCS is divided into four classes to medicine according to the height of the membrane permeability of its solubility and enteron aisle, high-dissolvability is classified as the primary standard of first kind medicine. The most solubility of Chinese medicine is lower, and membrane permeability is higher, belongs to the Equations of The Second Kind medicine among the BCS. Former chairman of American Pharmaceutical Association points out that the discovery of medicine and researcher will pay close attention to the situations such as solubility of medicine from the beginning, thereby before can avoiding the later stage clinical and the failure of clinical research, improves the success rate of new drug development. (Chinese Medicine, 2002.8.10,8 editions. ) therefore, the height of jamaicin solubility too can be directly has very important impact to the size of its bioavilability and range of application and clinical efficacy.

Most of jamaicin was once produced injection as the human antimicrobial, because of meeting generation serious adverse reaction, even the causing death. For this reason, the hydrochloride of jamaicin, citrate and sulfate injection all were deactivated before more than ten years, only kept the Berberine bisulfate parenteral solution and used once in a while, were also eliminated gradually. After this, people are long-term taking Berberine hydrochloride (such as the Berberine Hydrochloride Tablets of Zhongyi Pharmaceutical Industry Co., Ltd's production) still, but its solubility is very little, and oral absorption is very poor, and blood concentration is very low, only is used for antibiotic. Though the jamaicin that other several solubility are higher is soluble in water, oral absorptivity is good, can the drug effect of giving full play to is mainly made antimicrobial for animals (such as the berberine sulphate parenteral solution for animals of Jiangxi people's star animal health-care product Co., Ltd production) or made chemical reagent. Country expressly provides: people's medicine, veterinary drug must strictly separate, forbid using with; Chemical reagent does not belong to medicine, must not be used for medical treatment. Up to now, oral " berberine " in clinical use and pharmacy's sale all is single Halomine. Therefore, " berberine " of human long-term taking be Halomine in fact still, does not comprise other berberine as veterinary drug and reagent. " berberine " that it has often been said only is the abbreviation to Halomine, then indicates its full name on medical books and periodicals and this drug package thing. For a long time, medicinal berberine signs at NF or Arzneibucs or veterinary drug standard or this medicine bottle that all only to state clearly be that " antimicrobial is used for enteric infection. " even the pharmacy corporation of producing various berberines in the operation instruction of its product (bulk drug or people, animal medicine etc.) and the scope of application except antibiotic purposes of the not mentioned human treatment's of can be used for Other diseases all.

The solubility that all shows berberine from zoopery and clinical testing is higher, and bioavilability is larger, and pharmacological action is stronger, and result for the treatment of is better. But the mankind can not take the formed technology prejudice of veterinary drug and continue decades so far, cause people not go to consider that animal drugs is used for the treatment of the possibility of human body diseases, hinder for a long time people to the research and development of this technical field. If the high-dissolvability jamaicins such as berberine sulphate for animals are improved formulation, be prepared as the non-injection medicine of human, greatly change the method for administration of this material, the bioavilability of its active material is improved, toxicity reduces, stability increases, and the solubility that adds them has improved manyfold than the Berberine hydrochloride of human, can promote drug absorption, give full play to drug effect, impel curative effect to increase substantially, can enlarge medical application thus, be widely used in treatment and the human various diseases of prevention. The author has applied for and discloses two patent of invention (application numbers: 03123336.8 and 03148833.1) that adopt high-dissolvability jamaicin treatment diabetes, infectious diseases and obesity. But the new purposes of high-dissolvability berberine runs far deeper than these scopes, also can develop other treatment indication.

Summary of the invention

The object of the present invention is to provide the new purposes of high-dissolvability jamaicin in preparing treatment or the Other diseases medicine of prevention except diabetes, infectious diseases and obesity. Described jamaicin also comprises the jamaicin of high-dissolvability and the various jamaicins of citric acid jamaicin, Berberine bisulfate, berberine sulfate and phosphoric acid jamaicin and extraction from plant, chemical synthesis or the acquisition of other method.

The berberine of described high-dissolvability refers to the jamaicin that can dissolve in less than 500 parts of (weight, lower with) water, preferred jamaicin is that the solubility in water is 1: 100, preferably 1: 30 1: 15 even.

In fact, the present invention relates to the application of high-dissolvability jamaicin in the medicine of preparation treatment or preventing hypertension.

Relate to the application of high-dissolvability jamaicin in the medicine of preparation treatment or prevention high fat of blood.

Relate to the application of high-dissolvability jamaicin in preparation treatment inhibition platelet aggregation or antithrombotic medicine.

Relate to the high-dissolvability jamaicin in preparation treatment or prevent application in the ARR medicine.

Relate to the application of high-dissolvability jamaicin in the medicine of preparation auxiliary curing or prevention of cardiac.

Relate to the application of high-dissolvability jamaicin in preparing the atherosis medicine of auxiliary curing or prevention of arterial.

Relate to the application of high-dissolvability jamaicin in the medicine of preparation auxiliary curing or prevention cardiovascular and cerebrovascular disease.

Relate to the application of high-dissolvability jamaicin in the medicine of preparation auxiliary curing or prevention hepatitis.

Relate to the application of high-dissolvability jamaicin in the medicine of preparation auxiliary curing or the dirty disease of prevention courage.

Relate to the application of high-dissolvability jamaicin in the medicine for preparing auxiliary curing or prevention urine albumen, ephrosis.

Also relate to the application of high-dissolvability jamaicin in the medicine of preparation auxiliary curing or pre-preventing tumor and cancer.

The specific embodiment

In one embodiment of the invention, described jamaicin also can obtain through chemical synthesis or other method except extracting from plant.

In another embodiment of the invention, select any or two or more high-dissolvabilities (can in less than 500 parts of water, dissolve) jamaicin (comprising citric acid jamaicin, Berberine bisulfate, berberine sulfate and phosphoric acid jamaicin) bulk drug powder to be prepared into according to a conventional method medicine; Can use also that the non-injection medicine that any above-mentioned jamaicin bulk drug and other any material (the acceptable auxiliary material of medicine or pharmacy) make up according to a conventional method or prepare (comprising oral, for oral administration and external preparation)---oral formulations wherein comprises capsule, tablet, pill, dripping pill, nanometer, micro-capsule, electuary. Each oral berberine 0.4～1.2g that is grown up, every day 3 times. Add once in case of necessity.

The medicine of the high-dissolvability jamaicin preparation that the present invention uses also has following beneficial effect:

1, safety of medicine is efficient: these jamaicins are soluble in water, can be absorbed fully by body, so blood concentration increases, bioavilability improves thereupon, can give full play to drug effect, on curative effect, significantly surpass Berberine hydrochloride commonly used, particularly berberine sulphate is improved to the mouth preparation, the serious adverse reaction that can avoid administrated by injection to bring is taken very safe. In addition, after in test hyperglycaemia, hypertension, high fat of blood, high heart rate being down to normally, in order to keep treatment, no matter continue length medicine time, hypoglycemia, low blood pressure, hypolipemia, low heart rate response all do not occur in the dosage size, show that berberine has autoregulation, with relevant Western medicine contrast, security is higher.

2, meet quality standard: they are definite to curative effect of disease such as diabetes, hypertension, the steady quality of medicine, and side effect is slight. Get owing to its raw material adopts single medicinal material to extract, active ingredient is clear, and effect clearly has controlled quality standard, meets the international quality standards of " safe, effective, controlled, stable " that medicine should possess, also is the unitary basis of the modernization of Chinese medicine.

3, medical application is extensive: the jamaicin that the present invention adopts is very wide to the purposes of human body, except can reduce blood sugar, fat-reducing, antibiotic etc. also to tumour or cancer, the heart, the cranial vascular diseases such as liver, courage, kidney trouble, thrombocyte cohesion and hypertension, high fat of blood, heart disease, arrhythmia cordis, atherosclerotic have preferably auxiliary curing and prevention effect, are a kind of multi-functional potential new drugs that has.

4, available documents and materials: the pharmacology of various berberines, toxicity, effect, side effect are identical, and the main quality index of several jamaicins commonly used is all identical (seeing Table 3) also. Write articles according to people such as Dai Shen: " at new drug development with in declaring, selecting and utilizing documents and materials is very important work. It can be used by oneself existing technology and method etc. in development, research work is avoided detours, pick up speed. In declaration material, in identical situation aspect pharmacology, the toxicity, documents and materials can replace experimental data, as the foundation of new drug reviewing; Carry out this work and can reach the effect of getting twice the result with half the effort. " (medicine is declared and is examined application manual---and knowledge question is declared and examined to relevant new drug, imported medicine, imitation medicine, Chinese Medicine science and technology publishing house, February in 2000 the 1st edition, 58. ) according to above-mentioned instruction, simultaneously bound drug solubility determines the factors such as the theory of its curative effect and clinical practice actual effect, shows that the medicine of high-dissolvability berberine preparation is at the Halomine that can significantly be better than, be equal at least low solubility aspect various new purposes and the curative effect. Select used Halomine and utilize citric acid berberine and berberine sulphate (seeing Table the document [61] in the 1) related data of once making injection to declare new drug, can omit a large amount of energy, program, time and expense.

The invention has the advantages that:

1, the present invention has excavated new medical usage to high-dissolvability berberines such as veterinary antibacterial and chemical reagent, has opened up many-sided application prospect.

2, the medicine material source of the present invention's use is abundant, and preparation technology is simple, low production cost, and pharmacological action is very strong, and bad reaction is slight, and range of application is wide. Berberine belongs to non-prescribed medicine and lists medical insurance medicine product catalogue in, will be subject to the welcome of extensive patients, is widely used.

Embodiment 1

Old * *, the woman, 60 years old, in on February 21st, 2003 because of careless tumble injury admission examination, find the multiple complications such as left hand fracture of upper arm and diabetes B (fasting blood-glucose is up to 23mmol/L) and left eye fundus hemorrhage, cataract, detachment of retina, serious hypertension, immediately insulin injection control blood sugar, other sick and wounded symptomatic treatment. The patient requires to use the oral drug therapy diabetes repeatedly, and add the Chinese medicines such as berberine sulphate every day when on July 24th, 2003 beginning is keeping the proinsulin consumption. When fasting blood-glucose and 2h-plasma glucose are stabilized in good or general range (the blood sugar evaluation criteria is with reference to the Asia---Pacific region diabetes control target: 1. good: on an empty stomach≤6.1mmol/L, after the meal 2h≤8mmol/L; 2. general: on an empty stomach＞6.1≤7mmol/L, after the meal 2h＞8≤10mmol/L. Because hypoglycemia never occurs in the Chinese medicines such as oral berberine, so the lower limit of not taking. ) subtract at every turn and use insulin 2u. Adhering to that berberine does not add does not subtract, and insulin only subtracts and do not add. The insulin until on February 2nd, 2004 thoroughly stopped using uses the berberine replacement therapy, overall process 193 days fully. After this still the Long-term Oral berberine is controlled blood sugar. Behind two wheat harvesting periods, in check on April 14th, 2004 glycosylated hemoglobin 6.1%, curative effect is more satisfactory. Oldly substitute insulin a year and a half so far fully with oral medicine, blood sugar, blood pressure are stabilized in normal range (NR) always, show that using berberine can effectively control blood pressure; The therapy that berberine substitutes the diabetes B insulin injection gradually is hopeful to realize that its mechanism may " have the effect that promotes beta Cell of islet regeneration and functional rehabilitation " relevant (this specification table 1 document [3]) with it.

Embodiment 2

The type 1 diabetes oral drugs are invalid, and use of exogenous insulin is the conclusion of domestic and international medical circle always all the life. Trouble when the patient generally feels to inject and misery are looked forward to and can be controlled blood sugar with oral drugs. High-dissolvability berberine (being called for short the A medicine) (is called for short the B medicine with the Chinese medicine glycosidase inhibitor, see and annotate 1) and have herbal mixture (the abbreviation C medicine of regulating function, recovering organism balance, see and annotate 2) unite and take, type 1 diabetes patient and pancreas are increased when keeping the Proinsulin consumption by the Partial Resection person hypoglycemic reaction occurs after taking said medicine, show that oral drugs have hypoglycemic activity equally to type 1 diabetes.

Guangxi is yellow * *, the woman 24 years old, suffered from type 1 diabetes 12 years, the concurrent PVR of left eye and losing one's sight. Every day, insulin injection 36u added A, B, C medicine when keeping insulin dosage in 10 days Mays in 2004.

Beijing king *, the woman, 35 years old, suffered from type 1 diabetes 7 years, every day, insulin injection 58u added A, B, C medicine in 19 days Augusts in 2004, subtracted when glucostasis at every turn and used insulin 1u, and once decrement was to 49u every day.

The Pucheng poplar * *, woman, 50 years old, because Biliary Calculi causes pancreatitis, cut 2 years of pancreas, every day insulin injection 20u, be about half of the general amount of insulin secretion of normal person, be equivalent to the type 1 diabetes people half, in 23 days June in 2004, added A, B, C medicine.

There are many common ground in Huang, king, three patients of poplar: they are long-term also to use insulin to keep blood glucose balance according to doses regularly, hypoglycemic harm particularly occurs in side effect that the misery when they look forward to breaking away from injection and application insulin produce sometimes, they thirst for having oral medicine to replace injection drug, they are ready to try out A, B, the C medicine that I provide free, all be about adding with 3 weeks of oral medicine, hypoglycemic reaction to occur, but all dare not eat sugar and alleviate hypoglycemia, and all dare not reduce or continue to reduce insulin dosage, all abandon continuing to use oral drugs, final all the maintenance according to original custom or recovery insulin dosage in the past. For various reasons, above-mentioned test case seldom and do not carry through to the end, the unknown finally could accomplish the end in view, but the fact that oral medicine can make type 1 diabetes patient blood sugar descend can be affirmed. Otherwise these medicines should have no effect after adding, and have eaten and have eaten free, can not subtract and use insulin, also hypoglycemia can not occur, and cause that thus the author is to the query of invalid this conclusion of type 1 diabetes human oral medicine. For a long time, insulin for treating diabetes has been brought into play huge effect, has saved many diabetics' life, is the specific drug of internationally recognized treatment diabetes. For this reason, in history once 1904,1923, nineteen forty-seven, 1958 to the finder of the researcher of pancreatic secretion liquid and insulin with continue the researcher and issued four Nobel Prizes (Chinese Medicine, 2001.11.13,8 editions). If can use no or little insulin for treating diabetes from now on, will be subject to the welcome of extensive patients, can declare too international Grand Prix (annotating 3).

Embodiment 3

China * *, man, 63 years old, diabetes B patient, the chronic nephritis that occurs together and slight coronary sclerosis heart disease. On inspection, fasting blood-glucose 10.5mmol/L, 2h-plasma glucose 13.8mmol/L, glucose in urine ++, urine albumen ++. Oral berberine sulphate after 3 months blood sugar be down to normal range (NR), glucose in urine, urine albumen are all negative. In addition, China is private prosecution again, and uncomfortable in chest, the palpitaition that originally occured now and then, angina pectoris and DE phenomenon (the Male sexual erection miasma of diabetes patient and the elderly Chang You hinders) are obviously improved. According to one's analysis, may be that berberine has direct hemangiectasis, due to the effect that stimulates circulation.

Embodiment 4

Arrhythmia cordis person's (nodal tachycardia) 7 people, male 4 people wherein, women 3 people; Heart rate the palpitation and restlessness symptom all occurs between 105～140 times/minutes. Oral berberine sulphate all is down to normal (60～100 times/minutes) after 2～4 weeks gradually, and malaise symptoms disappears. Continue to take medicine and keep treatment, none the slow phenomenon of hole occurs.

Embodiment 5

Hyperpietic 15 people, systolic pressure 140～165mmHg, in various degree headache, dizziness all occur in diastolic pressure 90～110mmHg, failure of memory, palpitaition, breathe hard, the symptom such as uncomfortable in chest, insomnia, wherein 9 people have arrhythmia cordis (Dou Su) concurrently. Oral berberine sulphate is after 3～5 weeks, and blood pressure, heart rate all are down to normal range (NR). Continue medication treatment, low blood pressure do not occur.

Embodiment 6

Applicant oneself, the man, 59 years old, be diagnosed as diabetes B on November 16th, 1998 by hospital, fasting blood-glucose 12.7mmol/L at that time, glucose in urine +++, first berberine sulphate on probation is made into capsule, every 0.3g, and each serving 3～4,3 times on the one. Blood sugar begins to descend gradually after 4 weeks, and blood sugar recovery is normal after 8 weeks, and keeps stable. Because after this throughout one's life medication of diabetes continues to take each 1～2 for a long time, 3 times on the one, so far existing 7 years, fasting blood-glucose remained on 4.87～6.12mmol/L, postprandial blood sugar 6.5～9.2mmol/L, between the glycosylated hemoglobin 5.8～6.3%, all do not rise for a long time in normal range (NR), original hypertension is down to normally again, and the blood T-CHOL significantly reduces, the transference cures such as premorbid arrhythmia cordis, the uncomfortable in chest and numb pain of brothers (sometimes bitterly being waken up midnight) occur again.

Find again two rare phenomenons through observing to sum up in treatment: 1, To Be Protected from Heat, the hidrosis in summer in person, often shirt soaked. Its sweat core is dry easily through wind or Exposure to Sunlight, but stays the vestige that a circle is not done in sweat mark outermost, and is the most obvious with light clothes. Through check, confirm as the oil stain that goes out with sweat, but before taking berberine, all do not occur for many years being with oily phenomenon in the sweat, show that berberine can make body fat emulsification and excretes with excreta. 2, I from 1997 from the beginning of the 150 degree reading glasses of bringing into use so far existing more than 8 years still using, show that the eyesight of oneself did not go down. The diabetes patient has the ocular complications such as PVR, optic neuropathy more, but the severe patient blinding. The prompting berberine can improve hypopsia.

Embodiment 7

Adopt common process and auxiliary material to be made as tablet high-dissolvability berberine (preferably sulfuric acid berberine) bulk drug.

Embodiment 8

Adopt common process and auxiliary material to be made as capsule high-dissolvability berberine (preferably sulfuric acid berberine) bulk drug.

Annotate 1: Chinese medicine glycosidase inhibitor of the present invention is with the medicinal preparation for oral administration of the extract preparation of Cortex Mori etc., can reduce the common postprandial hyperglycemia of diabetes patient, and the mechanism of action of " visiing Tang Ping " with similar Western medicine is identical. Apply for a patent separately application number: 02126798.7.

Annotate 2: write articles according to people such as Han Ming: " kidney tonifying, yin-nourishing, beneficial gas, promoting blood circulation and removing blood stasisly be the treating diabetes fundamentum. " (treating diabetes and rehabilitation guide; China Traditional Chinese Medicine Publishing House; November in 1993 the 1st edition; 92) because Liuwei Dihuang Wan is the ancient prescription famous medicine of having used centuries; to enriching yin and nourishing kidney, improve the immunity determined curative effect; for this reason, add beneficial gas on the Liuwei Dihuang basis and Chinese medicine promoting blood circulation and removing blood stasis forms new compound, can meet treating diabetes fundamentum (number of patent application: 200510096764.6). On the other hand, in view of the rhizoma alismatis toxicity in the Liuwei Dihuang Wan larger, side effect is more, " renal toxicity that causes can cause acute tubular necrosis ", adopt the Chinese medicine root bark of Chinese wolf-berry that can rush down equally the kidney fire to substitute rhizoma alismatis, the effect of nourishing Yin and invigorating kidney that both can keep former side's Liuwei Dihuang Wan can be avoided again the many bad reactions (number of patent application: 200510092594.4) because using rhizoma alismatis to cause.

Annotate 3: see the paper " query invalid to the type 1 diabetes oral drugs " that the applicant delivers for details.

The part information of the new purposes of table 1. research Halomine

The researcher	Zoopery and clinical research	Document and sequence number
			Old its bright wisdom of thanking of institute of Materia Medica,Chinese Academy of Medical Sciences	Jamaicin has the characteristics of sulfonylureas and biguanide compound concurrently. Normal mouse, Spontaneous Diabetic mouse and alloxan diabetes mouse there is hypoglycemic activity. Can resist the blood sugar rising that Exogenous Glucose causes. Can be to adrenolytic blood glucose increasing effect. Hypoglycemic activity is stronger. Reach 5～6 hours action time. Can improve disturbance of blood coagulation, antiatherosclerosis. Jamaicin is existing obvious hypoglycemic activity when 40mg/kg, and this dosage is equivalent to 1/10th of median lethal dose.	Acta Pharmaceutica Sinica 1986; 21 (6): 401～406 [1]
Jamaicin does not increase the insulin secretion of normal mouse, do not increase to the insulin behind the glucose load yet and discharge, on normal mouse liver cell film insulin receptor number and affinity all without impact, thereby may be to reduce mouse blood sugar by the acceptor aftereffect, also may be to produce hypoglycemic activity by the gluconeogenesis that suppresses liver and/or the glucose glycolysis that promotes peripheral tissues.	Acta Pharmaceutica Sinica 1987; 22 (3): 161～165 [2]
		PLA's the 208th Ni Yan of hospital rosy clouds etc.		Berberine in treating diabetes B (lower with) 60 examples, 1～3 month course for the treatment of, the fasting blood-glucose 5.1mmol/L that on average descends, total effective rate 90%. The observation of animal pathologic finding beta Cell of islet shows by experiment, and the coptis have the effect that promotes beta Cell of islet regeneration and functional rehabilitation. Liver, renal function and blood picture all change non-evident effect without unusual during all patients treatment.	Combination of Chinese tradiational and Western medicine magazine 1988; 8 (12): 711～713 [3]
Jiujiang city Pengze institute of traditional Chinese medicine Liu state should	Treat 30 examples, efficient 90%. To light, moderate diabetic is evident in efficacy. Have simultaneously hypotensive, reducing blood lipid, anti-infective, prevent the effects such as complication. Japanese scholars experiment showed, that berberine short cancer material capable of blocking is transformed into real cancer cell to having potential short cancer cell, can play a great role to anti-cancer.		Old medicine is new for 1992; (1): 3～4 [4]
		Beijing builder hospital is in cotton flourish etc.		Treat 75 examples, efficient 69.33%, all cases " more than three " symptom disappeared in two weeks of taking medicine, and is consistent fall time with blood sugar. Observed the diabetic 4 years with Berberine in treating, no matter dosage is big or small, side effect or hypoglycemia occur without 1 example. Wherein 11 examples subtract dosage and kept more than 3 years, and blood sugar is normal.	Beijing medical science 1994; 16 (2): 117 [5]
Shan County, Henan Hu Faguang of the People's Hospital etc.	Treat 60 examples, total effective rate 90%, this medicine blood sugar reducing function is gentle, and about two weeks beginning hypoglycemic reaches greatest treatment efficacy in 8 weeks and lasting, and all cases diabetic symptom all disappears or alleviates, and its common complication is had good result. The super body severe one of 4 examples becomes normally. Without serious toxic and side effect. Angiocardiopathy there is important curative effect.		Practical combination of Chinese tradiational and Western medicine magazine 1995; 8 (6): 358～359 [6]

Continued

The researcher	Zoopery and clinical research	Document and sequence number
			Xing of the People's Hospital, Huantai County, Shandong Province Sinology	Berberine tablet is treated 33 examples, after 3 weeks of medication, and 30 examples, 2 type patient " more than three " transference cures. 3 examples, 1 type patient blood sugar descends, and the injection of insulin number of times is kept to 2 times by 3 times, and dosage reduces. Observe more than 3 months without obvious adverse reaction.	The traditional Chinese medical science is taught by correspondence communication 1997; 16 (2): 22 [7]
Deng Wenlong	Jamaicin can reduce blood sugar, and the mechanism of its blood sugar reducing function and insulin are irrelevant. Can treat and prevent diabetes and complication thereof, hypertension, high fat of blood, arrhythmia cordis, angina pectoris, heart failure, VPB, atrial premature beats, atherosclerotic; the multiple angiocardiopathy such as platelet aggregation and hepatitis, tumour, cancer, septicaemia; maincenter calmness, local anaesthesia are arranged, resist the effect of putting, irradiation causes dead mouse to Co 60 protective effect. Toxic liver injury due to the industrial poison there is certain protection effect. Remarkable anti-inflammatory activity is arranged, antibacterial during low concentration, sterilization during high concentration. Can prevent and treat gastritis, gastroduodenal ulcer, enteric infection, bacillary dysentery, diarrhoea, cholera, ileotyphus, balantidium Coli disease, cholecystitis, infection of biliary tract, respiratory tract infection, lobar pneumonia, infantile pneumonia, lung abscess, pulmonary tuberculosis; Acute/chronic bronchitis, pleurisy, diphtheria, influenza, pertussis, the Alba bacterium infects, candida albicans infection, renal plevis, ephritis, the cutization pyogenic infection, carbuncle, furuncle, ruffian, abscess, adenolymphitis, the pyogenic infection of the pad of a finger, mastitis, impetigo, refer to osteomyelitis, the pyogenic infection of (toe) section of finger, infection of burn, vaginitis, adnexitis, cervical erosion, trachoma, conjunctivitis, the eyes-affinity blepharitis, sty, keratitis, tympanitis, otitis externa, rhinitis, the jaw sinusitis, the acute and chronic tonsillitis, oro-maxillo-facial inflammation, herpetic stomatitis, recurrent stomatitis, oral mucosa ulcer, put forth energy the Sen Shi stomatitis, Salmonella is sick in uncommon Shandong, leptospirosis, leprosy, scarlet fever, Hemorrhagic fever, various acute infections, severe infection, bacterial infection, the viral infection disease, digestive system, respiratory system, urinary system, dept. of dermatology, surgery, gynaecology, the multiple different pathogens such as ENT dept., different parts be not even with the infectious diseases of lesion nature.	Herbal pharmacology with use the king and bathe the chief editor People's Health Publisher such as Sheng Dengwenlong December in 1998 the 1st edition 1004～1019 [8]
			The Zhang Jiaqing of Changhai hospital of The 2nd Army Medical College	The coptis have certain increase insulin sensitivity effect, and Sensitivity Index alleviates insulin resistance near melbine.	The practical diabetes magazine 1999 in Liaoning; 1 (4) 56～57[9]
Linchuan city of Jiangxi province first hospital of traditional Chinese medicine Deng chess is defended	The berberine blood sugar reducing function certainly, but consumption should 25 slices/day or more than.	The friend 2002 of diabetes; (1): 42～43[10]

Continued

The researcher	Zoopery and clinical research	Document and sequence number
			The new medical college in Jiangsu	The coptis or jamaicin have inhibitory action to hemolytic streptococcus, meningococcus, Diplococcus pneumopniae, comma bacillus, bacillus anthracis, staphylococcus aureus, shigella dysenteriae, corynebacterium diphtheriae, hay bacillus, viridans streptococci, pneumobacillus, Bordetella pertussis, yersinia pestis, Brucella, clostridium tetani, Bacillus perfringens, tubercle bacillus, proteus, Escherichia coli, typhoid bacillus. Low concentration is antibacterial, the high concentration sterilization, and effect extensively can be used as anticorrisive agent. Once oral jamaicin 2 grams or coptis powder 100 grams have no any side effect. (purposes slightly)	Chinese medicine voluminous dictionary Shanghai science tech publishing house June in 1986 the 1st edition (volume two) 2022～2030 [11]
Lee of Academy of Traditional Chinese Medicine, Xinjiang is with justice	Coptis nature and flavor bitter cold, bitter can hot-temperedly wetting, the energy heat-clearing of trembling with fear, its main component jamaicin is hemangiectasis directly, loose vascular smooth muscle, antiadrenergic drug, promotion blood circulates smoothly, and the drying damp and strengthening spleen effect of similar motherland medical science goes phlegm also to change so wet. The product of clinical used clearing heat and nourishing yin all are to bring into play therapeutic action by the hypoglycemic that reduces phlegm.	All kinds of diseases and ailments all are born in phlegm Xueyuan Press March in 1991 the 1st edition 41,124[12]
			302 Wang Yong of hospital of Beijing PLA are happy etc.	Berberine is at first manually synthesized successfully in the world by China. Maximum characteristics are that side effect is little, for side effect reckling in the antidysenteric thing, the main organs such as liver, kidney, bone and nervous centralis are had no adverse effects.	The sick control 320 of common transmittable asks Golden Shield publishing house October in 1991 the 1st edition 36～37[13]
Dong three Bai Zhoulin are female	The coptis have extensive bacteriostasis, and loose smooth muscle and buck functionality are arranged, and can increase bile and form, and makes bile thinning, thus the performance choleretic effect. Also has anti-curare, adrenolytic. Can strengthen the effect of acetylcholine when low dose, heavy dose is then resisted it. Therefore, has again the atropine-like effect.	Food restriction or checking relation in five elements and diet compatibility and incompatibility of drugs China Light Industry Press November in 1991 the 1st edition 298～299[14]
			The huge state of Beijing Chinese Traditional and Western Medicine New Technology Inst. bright mansion army etc.	Jamaicin can be treated esophagitis, ischemic heart disease, meningococal meningitis, ulcerative colitis, Halophiles food poisoning, anal fissure, hedrosyrinx on every side inflammation, subcutaneous gangrene of newborn, skin ulcer, stubborn dermatitis etc. (all the other are with document 8)	The clinical complete works of China Traditional Chinese Medicine Publishing House of the new purposes of common drug January in 1994 the 1st edition 34～35,446～450 [15]
King's equality	Jamaicin and some derivatives thereof have active anticancer. Have antimicrobial and the antiprotozoan effect, the excited cat isolated heart of energy also increases coronary flow, can reduce the oxygen consumption of Mouse Liver, brain homogenate, can make animal organ's smooth muscle excited, strengthens cholinergic nerve.	Integrative Chinese-Western guide China Traditional Chinese Medicine Publishing House October in 1994 the 1st edition 23～25[16]

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			The Xie Hui people	Berberine is a kind of bitter tonic, can stimulate gastric secretion, helps digest. Cholagogic, expansion bile duct when promoting choleresis is discharged tiny cholelith, can make eat into fatty emulsification, evenly absorbed, turn round, distribute by stomach and intestine and be utilized digestion.	Shenyang evening paper 1995.6.24 [17]
Chinese Medical Sciences University's Liu Guoliang etc.	Antibiotic can reduce the requirement of insulin.	Diabetes the 1st edition 135[18 in actual China skill publishing house's June nineteen ninety-five]
			Jiao Wantian etc.	Berberine be it is generally acknowledged and had no side effect. On present data, what cause bad reaction is not berberine tablet but injection. It is dead that the oral a large amount of berberines of zoopery are unlikely.	The 1st edition 39～42[19 of adverse reaction of tcm and treatment People's Medical Officer Press's August in 1996]
Shen Li	But berberine step-down, lipopenicillinase, hypoglycemic, the control diabetic complication. Coronary heart disease and cerebrovascular disease due to the artery sclerosis are had important function, can improve body and press down cancer, anti-cancer ability, bacteriotoxin and cancer cell are had obvious antidotal effect. The old man who suffers from the diseases such as chronic colitis, polyp of colon, enteron aisle diverticulum, esophagitis often takes, and both can treat these illnesss, can prevent canceration again.	National medicine is reported 1999.1.8 [20]
			Li Wenjuan	For the invalid serious periodontitis pain of other Western medicine antibiotic therapy, the local topical berberine has special effect.	Shanghai Chinese is reported 1999.4.24[21]
Hu Xianguo	Berberine is controlled new purposes outward: recurrent oral ulceration, otitis media suppurative, eye conjunctivitis, prickly heat, child infectious diarrhoea, children's's mumps, children's's furuncle.	Medication economics is reported 2001.10.10 [22]
			People's Hospital of Weifang City, Shandong Liu of division of endocrinology Chang Mount etc.	Berberine has widely pharmacological action, such as antibiotic, antiviral, antimycotic, step-down, urine protein reducing, improves immunity of organisms and reaches cardiovascular effect, uses the berberine patient and does not find any side effect, and clinical practice is very safe. Stronger to the erythrocyte AR inhibitory action, neural, renal lesions there are obvious curative effects, to the control diabetic complication, will be a new road likely.	The practical diabetes magazine 2002 in Liaoning; 10 (3): 22～24 [23]
Just learning celebrating	Berberine tablet is controlled chronic prostatitis, oral 3 times of every day, each 3～4, serve on 3～6 months.	National medicine is reported 2003.4.18[24]

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			The Cheng Shu huge rocks such as affiliated hospital of Chongqing Medical institute etc.	Berberine is tried out in 12 routine typhoid patients, obtained satisfactory effect. Be easy to after berberine is oral in absorbed into serum and the tissue, quite high at the intestinal tissue intensive amount, be only second to the heart, kidney and classify the 3rd as, also can infiltrate the other parts of marrow, reticuloendothelial system, the liver spleen is dwindled. Use safe, economical.	CHINESE JOURNAL OF INTERNAL MEDICINE 1959; 7 (8): 744～749 [25]
The yellow big people of Xuhui District, Shanghai central hospital etc.	No matter from vitro test or to the result of high platelet aggregation rate patient clinical therapeutic test, prove that all berberine is inhibited to platelet aggregation. The oral medication that 160 routine platelet aggregation rates is increased the patient is efficient up to 95%.	Chinese Journal of Hematology 1989; 10 (5): 228～231 [26]
			Beijing Hospital Jiang state man of virtue and ability etc.	Chinese Drug Rhizomes of Coptis element hypoglycemic activity is obvious, blood sugar peak descending＞30.1%.	Practical diabetology People's Health Publisher September in 1992 the 1st edition 175[27]
The Liu Changshan such as Shandong Weifang Medical College etc.	The diabetic is along with the progress of the state of an illness, and most meeting produces renal failure. The Chinese Drug Rhizomes of Coptis element is evident in efficacy to the reverting diabetes renal lesions, and diabetic mice crystal, kidney aldose reductase (AR) activity are had remarkable inhibitory action, urine protein decreased (P＜0.01). Cheap and the non-evident effect of berberine will provide for the control of diabetes renal lesions a new way likely.	Diabetes mellitus in China magazine 1996; 4 (3): 163～166 [28]
			Liu of endocrine research department of Weifang Medical College Chang Mount etc.	Diabetic neuropathy can involve any nerve of whole body, is widely used at present the aldose reductase inhibitor treatment, but the side effects such as heating, allergy are arranged, and its value for clinical application is restricted. The zoopery berberine can obviously improve diabetic sciatic nerve conduction of velocity (P＜0.05), and effect is identical with aldose reductase inhibitor. Because the little prolonged application of side effect has more superiority.	Weifang Medical College's journal 1996; 18 (1): 19～22 [29]
Feng of People Hospital No.1, Jining City bolt woods etc.	120 routine Arteriosclerotic Cerebral Infarction patients take respectively Halomine and aspirin, the former rear platelet aggregation rate obviously descend (P＜0.001) of taking medicine, total effective rate 95%, similar to aspirin (efficient 90%), but aspirin is limited to the effect of prevention ishemic stroke, has shown that berberine is the anti-platelet aggregation agent more more superior than aspirin.	Shandong medicine 1996; 36 (2): 11～12 [30]

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			Anhui Province defends the Fengtai County the virgin golden flower in school	Berberine tablet treatment diabetes B 49 examples, total effective rate is 63.3%, can reduce sympathetic activity, adrenal cortex function there is inhibitory action, thereby make gluconeogenesis, decompose and reduce, insulin metabolism is slow, and surrounding tissue can promote again regeneration and the functional rehabilitation of beta Cell of islet to insulin sensitivity.	The new traditional Chinese medical science 1997; 29 (3) 33～34[31]
Colliery, Shandong Mount Taishan hospital poplar Ankang etc.	The treatment of hypercoagulable blood is difficulty comparatively, and medicine is a lot, but lacks a kind of rapid and stable medicine that acts on. 31 routine inpatients are with berberine tablets, oral 30 days, the as a result low value of cutting of WBV, plasma viscosity, packed cell volume, and fibronectin all decreases, and has differed conspicuousness (P＜0.05) before the treatment.	Chinese coal industrial medicine magazine 1998; 1 (1): 53[32]
			Ge Jianguo	The new purposes of berberine: anti-arrhythmia, chamber property and SA that many reasons is caused have good therapeutic effect; Treatment hypertension; The treatment hyperlipidemia is better than vs Duo-xi-kang, evening primrose oil; Treatment is in heart failure, platelet aggregation-against; The treatment diabetes are particularly suitable to the hypertension that occurs together, high fat of blood; The treatment peptic ulcer, better to Stomach duodenum duodenobulbar ulcer effect; Anti-cancer.	The healthy 1999.1.27,4 editions [33] of reporting
Hangzhou sanatorium of air force Zhang Yunfei	Diabetes B patient 20 examples change and take berberine tablet after OHA (such as D860, diabetes pill etc.) is not effectively controlled, and after 3 months, all patients fasting blood-glucose all is down to normally. Hypoglycemic effect and the consumption of berberine are proportional, when blood glucose value reaches normal level, also hypoglycemia can not occur in any case strengthen consumption. When OHA was invalid, using that oral berberine tablet can yet be regarded as instead was a kind of good trial.	China's combination of Chinese tradiational and Western medicine magazine 1999; 19 (9): 567 [34]
			The bright red Dai Wei such as The Hospital Attached to Jining Medical College	Treat 112 examples, efficient 90%. The proof coptis have definite blood sugar reducing function, and action temperature and and lasting, without serious toxic and side effect, without liver and kidney dysfunction, the diabetes common complication is all had good efficacy. Without impact, can not cause hypoglycemic reaction to euglycemia, be a kind of desirable hypoglycemic medicine that is worthy to be popularized.	Jining Medical College journal the 22nd volume the 3rd phase 67[35 September in 1999]
Qiao of hospital general is beautiful in Heilongjiang Province Qitaihe City cleaned coal group company	Treat 30 examples, total effective rate 90%. With examining 18 example half a year～1 year, 15 examples are kept treatment as a result, and are respond well; The 3 routine diet blood sugar that waits out of control rises again, through correcting diet, eliminates direct stimulation, and is all effective with Berberine in treating again. The berberine hypoglycemic activity is reliable, and the course of disease is shorter, and curative effect is better, has no side effect, and clinical have a promotional value.	Traditional Chinese medicine information the 1st phase 36 [36] in 2000

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			Jining of Shandong Province city First People's Hospital's Neurology silver is for army building etc.	Transient ischemic attack (TIA) is an important risk factor of cerebral infarction, the generation of this disease with lapse to platelet aggregation closely related. Observation group's 30 examples were treated 30 days with jamaicin, and platelet aggregation rate obviously descends, and TIA obviously reduces, and were the active drugs of prevention cerebral infarction. It is limited that aspirin is prevented and treated the effect of cerebral infarction, long-term taking can cause bleeding, canker etc., and jamaicin is more effective medicament for resisting platelet aggregation, and side effect is little, easily accepted for a long time by patient, can in the treatment of control TLA and other ishemic stroke, apply fully.	New medical science 1999; 30 (1); 19～20 [37]
The sharp sky of the stones such as Taiyuan City commercial worker hospital etc.	Treat 68 examples, blood sugar obviously descends, and total effective rate is g6.8%, and its hypoglycemic mechanism is many-sided, serum insulin level obviously raise (P＜0.01) after the treatment. Berberine has significant hypoglycemic effect to experimental animal models, and drug withdrawal still can be kept curative effect more than 7 days. Berberine is described anti-ly rises the C-21 cortico-steroid effect also and promote that beta Cell of islet regeneration and functional rehabilitation are relevant except having.	The clinical medical magazine in Shanxi the 9th volume the 3rd phase 181-182 in March [38] in 2000
			People's Armed Police Shanxi army unit internal medicine in hospital Zhang Jiying etc.	Hyperglycemia is one of key factor of diabetic complication. Clinical testing 78 examples, take heavy dose of berberine and the 34 example injection ligustrazines diabetic's Hemorheology that has clear improvement, berberine to reduce plasma viscosity, reduce erythrocyte aggregation index, packed cell volume, fibronectin and reduce the blood sugar aspect and be better than ligustrazine. Berberine is to high platelet aggregation rate patient's curative effect and the therapeutic equivalence of aspirin merging persantine, and side effect is little, and to improving microcirculation and Hemorheology, prevent or complication etc. played the effect of achieving many things at one stroke, the medicine source is wide, inexpensive, convenient, and application prospect is very wide.	People's Armed Police's medical science 2000-11 643～646 heavy dose of berberines are on the clinical research [39] of diabetes B hemorheology in patients impact
The Urology Surgery Tang Li of hospital general, Wuhan, the military region, Guangzhou merit etc.	Behind the renal transplantation, the patient needs the immunodepressant such as long-term taking ciclosporin A (CsA), but it is expensive, and certain toxic and side effect is arranged, and also can cause infecting and malignant tumour. If can reduce the CsA consumption, both can keep transplanted kidney function, can reduce economic cost again, significant to the transplant patient. Take the concentration that berberine can improve CsA, the blood concentration valley obviously raises, and compares significant difference, patient's routine blood test, normal renal function before and after taking medicine. Can reduce the CsA consumption.	China's organ transplant magazine the 2nd phase 109～110 [40] of the 22nd volume March calendar year 2001

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			Lee of hospital general, Wuhan, the military region, Guangzhou is used up etc.	The ciclosporin A price is very expensive, general every renal transplantation recipients is paid ciclosporin A 3～50,000 yuan every year, the ciclosporin A blood concentration can significantly increase behind the berberine HCl, the consumption of ciclosporin A is obviously reduced, take a turn for the better to some extent from the main renal function index of numerical value, forward normal range (NR) to by abnormal ranges. Show that two medicines share toxic action to kidney and have and subtract without increasing, improve and transplant (people/graft) survival rate, can reduce bad reaction, will greatly alleviate the burden of patient and society.	The Chinese Journal of Clinical Pharmacology the 6th phase 448～450 [41] of the 17th volume November calendar year 2001
The deep tin apple of hospital of Guangxi Liuzhou Iron And Steel company etc.	Berberine in treating diabetes B 32 examples, total effective rate 90.6%. The blood sugar reducing function of berberine is similar to Diamicron, efficiently is respectively 72.3% and 70%. Berberine share Diamicron curative effect (total effective rate is 95%) and is better than single drug.	China medical abstract clinical practice 2001; 22 (2): 267～269[42]
			The poplar Bao Feng of pharmaceutical college of Harbin Medical University etc.	Low dose of jamaicin can be used for the early afterdepolarizations that slight heart stalk brings out, and is heavy dose of then can be used for the severe heart and obstruct the arrhythmia cordis of bringing out.	The 2002.12.24.11 of Chinese Medicine version [43]
Taizhou City Mount Taishan, the Jiangsu Province king of the commune hospital winter detains	57 routine diabetics originally took second generation sulfonylurea drugs or share with melbine, (oral medicine dosage has reached height and has restricted water supply flat to occur secondary failure after 3 years, body is in long-term hyperglycemia state), through add berberine after 1 month blood sugar descend in various degree total effective rate 81%. Berberine in treating sulfonylureas secondary failure diabetes have preferably curative effect, can gradually reduce to occupy the sulfonylureas drugs for diabetes dosage that height is restricted water supply flat after fasting blood-glucose is down to normal level. Its treatment mechanism may can be resisted the hormone that blood sugar is raise with berberine, promotes that the beta Cell of islet excreting insulin is relevant, thereby makes beta Cell of islet break away from " glucose toxic state ", and improve insulin resistance.	Zhejiang combination of Chinese tradiational and Western medicine magazine 2002; 12 (1): 50 Berberine in treating Clinical Observation on Secondary Inefficiency of Sulfonylureas Drugs for Diabetes 57 examples [44]
			Pay the general Guo Qing of elegant celery Wang Fang peak etc.	If berberine share with antibiotic, can play the antibacterial action of addition in treatment respiratory tract or enteric infection; Have with playing collaborative the work together with respiration stimulant; The coptis have direct hemangiectasis, antiadrenergic drug and suppresses the effect of pressor reflex, inhibition vasomotor center, has share summation action with drug for hypertension; The application local anaesthetics adds uses berberine, can strengthen curative effect; The coptis have active anticancer, can suppress Ascitic Tumor Cells and breathe, and suppresses yellow enzyme, and inhibition cancer cell is to the effect of azanol, thereby synthesizing of inhibition purine and nucleic acid-protein can be strengthened curative effect as adding with berberine in anticancer chemotherapy.	Adverse drug reaction and interaction China Science Tech Publishing House thereof May in 2000 the 1st edition 309 [45]

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			The Yan Liu of Wu Li army literary composition	Although content of berberine is higher in the coptis, coptis growth cycle is long, and resource-constrained is difficult to satisfy the demands. Extracted the primary raw material of jamaicin as pharmaceuticals industry with the golden cypress of Rutaceae, the barberry of Berberis, the arcangelisia lourieiri of Menispermaceae afterwards.	Chemistry for Chinese Traditional Medicine Chinese Medicine science and technology publishing house June calendar year 2001 the 1st edition 49,210[46]
Yuanan County, the Hubei Province Hu Xianguo of institute of traditional Chinese medicine	Control chronic colitis outward, get 2 of berberines, grind and be smalls, add clear water and be adjusted in right amount pasty state, spread on umbilical region outward, use immobilization with adhesive tape. Change dressings every day 1～2 time, be used in conjunction 1～2 day, can be clearing heat and detoxicating, dampness removing and diarrhea-relieving.	The 2003.2.17 of Chinese Medicine, 10 editions [47]
			The old name of the Zhang Yibo of Shanghai City endocrine research institute road	The pharmacological action of berberine obtains research extensively and profoundly in decades; such as effects such as antibiotic, antiviral, anti-arrhythmia, protection ischemic myocardium, hypotensive, anti-gastric-ulcer, antitumor and anti-AIDS, the report of especially preventing and treating diabetes and complication thereof day by day increases (its mechanism of action remain further research). Jamaicin can suppress the hepatic glycogen decomposition reaction of insulin resistance rat, reduces blood sugar by increasing hepatocellular glucose utilization, and is non-insulin-dependent. Jamaicin and melbine have the effect of similar increase insulin sensitivity, are not to bring into play hypoglycemic activity by increasing insulin secretion. Berberine can reduce the rat blood serum insulin level, alleviates impaired glucose tolerance, reduces liver lipid peroxide (LPO) level, improves the activity of Liver Superoxide Dismutase Activity (SOD). It is anti-oxidant and remove the free radical ability to improve body, promotes the catabolism of lipid, significantly reduces the diabetes rat blood lipid level, serum cholesterol level obviously descend (P＜0.001). Can prevent and treat the complication such as diabetes renal lesions and vascular lesion. Someone gives 33 routine chronic liver disease complicated with diabetes patients oral berberine, blood sugar obviously descend (P＜0.01) after 3 weeks for the treatment of. In the diabetic, the hyperglycaemia that continues can cause intracellular calcium concentration to raise by number of ways, thereby causes multiple complications, and jamaicin can suppress the rising of the intracellular calcium concentration that norepinephrine, potassium chloride or H2O2 cause. The Diabetes Mellitus SD Rats animal model is urinated protein decreased after with Berberine in treating, becomes tool and has certain effect suppressing AR activity and reverting diabetes popular name for. Berberine to the normal person of blood sugar without hypoglycemic activity. Berberine group and melbine group treatment diabetes are without significant difference. (all the other omit)	Effect and the mechanism [48] of the hypoglycemic and control chronic complicating diseases of diabetes of China's traditional Chinese medicine information magazine the 10th volume 1 phases 83～85 berberine January in 2003

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			Huang Weimin etc.	Ventricular tachyarrhythmia 50 examples, the course of disease 2～20 years. All patients once used 1～6 kind of antiarrhythmic drug in the past, and majority are invalid, though a few peoples have certain effect, failed to adhere to medication but can't tolerate its side effect. Took separately berberine 3～30 days, average premature beat reduces by 50% above person's 30 examples (efficient 60%), and wherein 20 routine premature beats disappear, and 20 examples are invalid in addition, show berberine to VPB, even to intractable patient, certain result for the treatment of arranged also.	Practical internal medicine journal 1985; 5 (11): 587 [49]
Cant side etc.	Various arrhythmia cordis 45 examples of Berberine in treating, arrhythmia cordis complete obiteration 25 examples, effective 10 examples, total effective rate 77.78%. It all has preferably curative effect to the arrhythmia cordis that many reasons causes, and side effect is little, and is oral extremely safe.	Practical internal medicine journal 1986; 6 (5): 257[50]
			Nanjing pharmaceutical college gold Rong mythical bird like the phoenix is worn the beginning of spring	The coptis or its main component jamaicin have antibiosis and antiviral functions, the phagocytosis that strengthens leucocyte and liver reticuloendothelial system is arranged, have reduce blood pressure, the effect of coronary artery dilator and visceral vessel, calm and lax effect is arranged, also have the pharmacological actions such as cholagogic, analgesic, analgesia and anti-inflammatory.	Pharmacy question and answer (the first fascicle) People's Health Publisher September in 1987 the 1st edition 29～30[51]
Li Chunying etc.	Berberine in treating intractable ventricular tachyarrhythmia 56 examples, as a result take medicine rear premature beat of 30 routine patients disappears, and 20 routine premature beats reduce more than 50%, invalid 6 examples, total effective rate 89.29%.	Clinically assemble 1991; 6 (2): 70[52]
			Qiao Yucheng Jiang Gao unit	Light Moderate Essential Hypertension patient 53 examples of independent oral Berberine in treating, 3～5 days blood pressures begin to descend, and reach minimum, total effective rate 69.8% in 6～9 days.	Unique curative effect Shanxi science tech publishing house of 98 kinds of medicines February in 1992 the 1st edition 9[53]
Morning Wang Tao Wu Hui	Berberine can be killed helicobacter pylori, and gastric and duodenal ulcer is had preferably curative effect; Can control the arrhythmia of polytype, most antiarrhythmic drugs all have the shortcoming that weakens myocardial contractive power, and berberine then can be strengthened the convergent force of cardiac muscle, has much characteristic; Hemangiectasis reduces blood pressure, blood fat, prevents and treats artery sclerosis; Platelet aggregation-against, antithrombotic and ICVD.	KNOWLEDGE ON MEDICINE guide China Textiles Press May in 1999 the 1st edition 208～209 [54]
			Zhou Ziyong king's generation is auspicious etc.	Berberine hydrochloride (Halomine) is slightly soluble in water, is dissolved in hot water. Clinical enteric infection and the bacillary dysentery etc. of being mainly used in. Recently find also that this product has antiarrhythmic effect. Usage: oral. Forbid drug administration by injection, because quiet notes can cause blood vessel dilatation, the severe reactions such as blood pressure drops and inhibition heartbeat.	Newly organized common drug handbook Golden Shield publishing house December in 2000 the 3rd edition 660～661[55]

The researcher	Zoopery and clinical research	Document and sequence number
			Feng Yougen	The berberine in reducing blood glucose effect is obvious, can be used for treating diabetes B and complication thereof. Treat 30 examples, 1～3 month course for the treatment of, total effective rate 90%. Treat 68 examples, 60 days courses for the treatment of, treatment group patient is after diet control adds Berberine in treating, and fasting blood-glucose (FBG) is reduced to 6.7 ± 1.3 mM/ls, and relatively there were significant differences (P＜0.01) with simple dietetic treatment (11.5 ± 3.0 mM/ls). Serum insulin mean value rising remarkable (P＜0.01) after the treatment. Give the normal person of 20 routine blood sugar and take berberine, take medicine before and after FBG without marked change, the prompting berberine to the normal person of blood sugar without further falling hypoglycemic effect. Relatively treat diabetes B with berberine and Gliquidone, each 112 example of minute berberine group and Gliquidone group. The result shows, berberine group total effective rate 90%, and Gliquidone group total effective rate 93% shows that berberine and Gliquidone have identical curative effect. Be widely used at present the drug therapy diabetes Bs such as second generation sulfonylureas or melbine, still, after a period of time, have quite a few patient's curative effect to reduce gradually. Sulfonylureas drugs for diabetes or sulfonylureas are added diabetes B patient 57 examples of using the melbine secondary failure, add berberine keeping former basis with types of drugs and dosage, 30 days is 1 course for the treatment of, produce effects 36 examples after the treatment, effective 14 examples, total effective rate are 81%. Some hypoglycemic medicine has infringement to liver, is not suitable for being applied to treat hepatogenous diabetes. To chronic liver disease companion diabetic 33 examples of keeping on a diet invalid, oral berberine, inactive other hypoglycemic medicines during the treatment, FBG is down to 6.31 ± 0.72 mM/ls (P＜0.01) from 9.22 ± 1.7 mM/ls after 3 weeks, two hours blood glucoses are down to 9.302.53 mM/l (P＜0.01) from 15.0 ± 3.31 mM/ls after the meal, obtain satisfied curative effect. The mechanism of berberine blood sugar reducing function is not yet clear, may be that berberine is brought into play Link role between insulin and insulin receptor, original affinity is descended cause Hypoglycemic Action Due To Insulin to reduce the improved result of this obstacle. The researcher has observed the variation that 38 routine non-diabetic persons and 56 routine diabetics use berberine blood sugar and islet beta cell function after 3 days, the result shows, after the diabetes B patient uses berberine, front each the time point respective value of blood sugar is compared and is decreased significantly (P＜0.01), but insulin and C peptide are without remarkable increase; Blood sugar was without decline after the ND used berberine, and each time point respective value of insulin and C peptide has no significant change, and prompting has in the situation of some insulin in vivo, and berberine just can be brought into play hypoglycemic activity. This point is different from the sulfonylureas and the biguanides that use at present, may be to have improved beta Cell of islet perception blood glucose system so infer it, thereby hyperglycaemia is improved, and not reduce euglycemia. The diabetes B patient is behind Berberine in treating, and insulin level rose when blood sugar descended, and growth hormone content, Somatostatin raise. Berberine may be by effect Hypothalamus-pituitary-pancreas axle system, thereby blood sugar level in the control agent makes homeostasis stable, reaches therapeutic purposes.	The 2003.8.21 of Chinese Medicine, 11 editions " coptis is said blood sugar effect progress " [56]

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			Hangzhou PLA the 117th Feng You of hospital root	The berberine antiarrhythmic effect is clear and definite, and is obvious to the curative effect of tachyarrhythmia. The bad reactions such as blood vessel dilatation, blood pressure drops, Cardiac depression can appear in the quiet notes of berberine or quiet, and Ah's spira's syndrome occurs when serious, can cause death and die; Quiet notes also can cause kidney function damage, even cause uremia; Intramuscular injection does not reach valid density. The berberine Orally-administrable, safe, easy, toxic and side effect is little, but long-term taking.	The application [57] of the 2003.3.18.11 of Chinese Medicine version berberine aspect anti-arrhythmia
The researcher increases the patient to 22 examples, 181 examples, 160 routine platelet aggregation rates respectively, and to give berberine oral, treated effect 95%. Berberine is brought into play its anti-aggtegation by acting on hematoblastic release function. At present the control of diabetic neuropathy (DN) acquired a certain degree of difficulty, and without specific medicament. Berberine has remarkable role of correcting to the MNCV of DN rat. The diabetic is after 4 all Berberine in treatings are used on the basis of using hypoglycemic medicine, and nervimotion conduction of velocity and sensory conduction velocity obviously improve in patient's median nerve, the calf. Berberine can make the urine protein decreased, is improved the renal lesions effect.	The 2003.10.21.11 of Chinese Medicine version berberine can be prevented and treated diabetic complication [58]
		Sick sinus syndrome is first-selected atropine, isoprel in treatment, but effect is still unsatisfactory. If implant a pacemaker, because of somewhat expensive, be difficult for being accepted by most of patients. Berberine share meglumine cyclic adenylate or berberine and calcium agent 5 usefulness, has the collaborative P of adjusting cellular metabolism, improves the important function of the sinus node function of Sick Sinus Syndrome, and non-evident effect.		The 2004.7.10.7 of the Chinese Medicine version berberine attitude sinus syndrome [59] of curing the disease
Chen Zheng	Beijing University of Chinese Medicine studies confirm that: jamaicin has stronger immunosuppressive action, and the multiple effects such as cell activation, intracellular signal transduction and the cell-membrane receptor expression of inhibition are arranged. Also the expression of the adhesive attraction of HL and huve cell and adhesion molecule CD18, CD44, E-Selectin, intercellular adhesion molecule-1 (ICAM-1) etc. there is obvious inhibitory action, can suppress the generation of sensitized mice cytokine profiles, immune a plurality of links are all had stronger immunosuppressive action.				The 2004.4.17 of Chinese Medicine, 7 editions [60]

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			The volumes such as Nanjing Medical College	Berberine is usually used in enteric infection and bacillary dysentery clinically, and preparation has berberine hydrochloride sheet, berberine structure same regimen acid salt parenteral solution, Berberine sulfate parenteral solution. (applicant's prompting, the berberine injection is now superseded)	Clinical medicine handbook Shanghai science tech publishing house in June, 1979 new 1 edition 45～46[61]
(lacking)	Section of PLA treatment Stomach duodenum Ulcer in 26 Patients, plyability ulcer 4 examples, with berberine 0.5 gram, three times on the one are oral, and 20～30 days is a course for the treatment of, and epigastric pain disappeared average 19.6 days, 4 all cure rates 67.6%.	The family doctor reports 1998.3.15 [62]
			Hospital Attached to Shandong Chinese Medical Univ.	Halomine has antitumor action, but inducing leukemia HL one 60 Apoptosis. P53 gene and relation between tumor are close, the sudden change inactivation that has the P53 gene among the human tumor cell more than 60%, the sudden change and the lump that have detected P53 in the kinds of tumors such as liver cancer, osteogenic sarcoma, lung cancer, colon cancer, neurofibrosarcoma, brain tumor, breast cancer and rhabdomyosarcoma lack. BcI-2 is a kind of new oncogene, and its high expressed can cause tumour. Jamaicin can suppress BcI-2 gene expression and promote the expression of P53 gene, and this may be one of anticancer dominant mechanism of jamaicin.	The 2005.6.11 of Chinese Medicine, 7 editions new set forth [63] of the anti-cancer of the stomach mechanism of berberine
The trials such as the chief editor such as a Su Kaizhong purple hole	Berberine has multiple pharmacodynamics effect and uses. The anti-arrhythmia principle may can make heart rate descend with to affect calcium sodium running relevant, and MCO reduces. The low dose of coptis have the effect that strengthens acetylcholine, and heavy dose is then resisted it. The clinical practice new development: 1, congestive heart failure, the coptis have and strengthen mammal cardiac contractility effect, have stronger positive inotropic action; Can make cardiac ejection fraction increase approximately 50%, heart rate descends, and whenever the amount of fighting increases, and improves depleted ventricular function, and is all effective to chronic congestive heart failure and acute heart failure. 2, the hemorrhage and miocardial infarction of cardiac muscle has the effect of protecting the myocardial damage that causes because of myocardial ischemia, and the coronary artery bar that high K+ is shunk has obvious relaxation effect, and coronary flow increases, and can treat ischemic heart disease. 3, very wide to ARR therapeutic domain, to chamber property, supraventricular, the lung arrhythmia is all effective; The Heart Failure in Pulmonary Heart hospitalizing take berberine after 3～6 days electrocardiogram recover normal, atrial fibrillation, sino atrial block disappear, the premature beat number of times reduces, repeatedly electrocardiogram is followed up a case by regular visits to and is had no recurrence. Berberine has good therapeutic index aspect angiocardiopathy, obtained certainly having certain prospect in a large amount of zooperies. Domestic this product drug administration by injection of having forbidden is only for oral or external application.	Old medicine is newly with 110 kinds of Fujian science tech publishing house April in 1989 the 1st edition 266～269 [64]

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The researcher	Zoopery and clinical research	Document and sequence number
			(lacking)	Halomine has inhibitory action to the tumour cell of some types. COX-2 (COX-2) is the emphasis of present tumour educational circles and the research of digestion educational circles, and it is considered to a kind of important tumour and regulates factor. Berberine can suppress the COX-2 activity, and then suppresses Prostaglandin PGE2Generation, this may suppress for berberine one of mechanism of HT-29 Growth of Colon Cancer Cells and propagation.	The 2003.9.2 of Chinese Medicine, 14 editions CHINESE JOURNAL OF INTERNAL MEDICINEs 2003.41 (8) [65]
Jiang of molecular biosciences research institute of the Chinese Academy of Medical Sciences builds the attached First Hospital Wei Jing of capital, southeast medical university etc.	Angiocardiopathy is to threaten one of the most serious disease of human health on the our times; The atherosclerotic that hyperlipidemia causes is to cause the main cause of coronary heart disease, hypertension and cranial vascular disease. The statins that uses at present can effectively reduce blood fat, but has the side effect of muscle injury and liver, and unsatisfactory to the effect of part patient reducing blood lipid. For inquiring into the effect for reducing fat of Berberine hydrochloride, 68 routine combined hyperlipidemia familial patients are divided into Berberine hydrochloride group 34 examples and his spit of fland lipid lowerers control group 34 examples, treated three months, the former can make patient's cholesterol, low-density lipoprotein and triglycerides descend 20～35%. The prompting jamaicin has good accent fat effect, and some aspect has more advantage than lipid-lowering statins. The jamaicin security may become the alternative medicine of statins beyond any doubt, and be expected to for statins therapeutic alliance angiocardiopathy.	Health is reported 2005.1.12,1 edition 2005.1.18 of Chinese Medicine, A5 version 2005.9.24,5 editions Chinese diabetes magazines 2005; 13 (1): the research [66] of the accent fat effect of 49～50 Berberine hydrochlorides
			Jiang builds the Eastern Wei Dynasty and respects etc.	The characteristics of berberine maximum are that side effect is extremely rare. Can interact and significantly improve the expression of insulin receptor gene and peroxisome MF activated receptor (PPARr) gene with insulin receptor, thereby can be the insulin sensitizer of 2 type diabetes, and can unite with insulin or other 2 type Remedies for diabetes separately and be used for the treatment of diabetes B.	Chinese patent communique berberine is as purposes application number 01121906.8 publication number 1393264 [67] of insulin sensitizer
Hard Cai of the Xian Li of Zhongshan Univ. Cancer Cure Center is in treasure	Berberine hydrochloride is usually used in infectious diseases, also is widely used in the treatment of the diseases such as peptic ulcer, arrhythmia cordis, diabetes, platelet aggregation-against, hypertension, thiacetazone side reaction, intractable bacillary dysentery, cervical erosion now. Especially aspect cardiovascular system; myocardial ischemia and miocardial infarction had protective effect; and can reduce arterial pressure; increase coronary flow; stream in the cardiac Ca2+ there is dual regulation; have simultaneously anti-radical action, to the protective effect of cerebral ischemia, antidiabetic effect and anti-tumor in vivo effect. Oral jamaicin can reach effective tumor suppression concentration, suppresses preferably the growth of S180 sarcoma in the kunming mice body, and suppresses human nasopharyngeal carcinoma CNE2 cell and the growth of people's colon oncocyte in the nude mouse body. (experimental diagrams slightly)	New purposes application number 02134693.3 publication number 1421203 [68] of the anti-tumor in vivo effect of Chinese patent communique jamaicin

The main jamaicin overview table of table 2.

The bulk drug title	Solubility in water		Present main application
				Berberine hydrochloride (Halomine)	1∶500	Low	1. human or antimicrobial for animals are used for enteric infection. 2. chemical reagent.
Citric acid jamaicin (citric acid berberine)	1∶125	High
			Berberine bisulfate (Berberine bisulfate)	1∶100
Berberine sulfate (berberine sulphate)	1∶30
			Phosphoric acid jamaicin (phosphoric acid berberine)	1∶15

Annotate: (1) dissolubility data draws from " Chemistry for Chinese Traditional Medicine ", the Wu Lijun chief editor, and Yan Liu's literary composition is write articles, Chinese Medicine science and technology publishing house, 2001,48.

(2) standard of Berberine solubility of the present invention height with the dissolubility data of human drugs Berberine hydrochloride in water for circumscribing.

(3) high-dissolvability jamaicin of the present invention refers to the various jamaicins that can dissolve in less than 500 parts of water.

Table 3. is commonly used the main quality index of jamaicin

Title	Proterties	Mainly contain the effective constituent content of berberine	Main harmful components content of beary metal	Classification (formulation)	The standard source
						Berberine hydrochloride	Yellow crystalline powder; Odorless, flavor are extremely bitter	The product of extraction must not be less than 97.0%, and composite must not be less than 98.0%.	Must not cross 20/1000000ths	Antimicrobial (tablet, capsule)	Two ones 548～549 of health ministry pharmacopoeia commission Chinese Pharmacopoeia versions in 2000
Berberine bisulfate	The yellow crystal powder; Flavor is extremely bitter.	The product of extraction must not be less than 97.5%, and composite must not be less than 98.0%.	Must not cross 20/1000000ths	Classes of anti-infective medicine (parenteral solution)	The ten WS-1001-of Bureau of Drugs Supervision's national drug standards (HD-1028) of country-2002 11-63～11-64
						Berberine sulfate	The orange colour crystalline powder; Odorless, flavor are extremely bitter	Must not be less than 98.0%.	Must not cross 20/1000000ths	Antimicrobial (parenteral solution)	One one 262～263 of country's department of agriculture and forestry veterinary drug standard version in 1978

(in this manual reference and quoted many experts and scholars' achievement in research of applicant is thanked you in the lump at this. )

Claims (10)

1, the application of high-dissolvability berberine in the medicine for preparing treatment or preventing hypertension, high fat of blood.

2, the application of high-dissolvability berberine in preparation treatment or prevention platelet aggregation or antithrombotic medicine.

3, the application of high-dissolvability berberine in preparing treatment or prevention arrhythmia cordis, cardiopathic medicine.

4, the high-dissolvability berberine is in the preparation auxiliary curing or prevention of arterial is atherosis, the application in the medicine of cardiovascular and cerebrovascular disease.

5, the application of high-dissolvability berberine in the medicine for preparing auxiliary curing or prevention hepatitis, the dirty disease of courage.

6, the application of high-dissolvability berberine in the medicine of preparation auxiliary curing or prevention urine albumen and ephrosis.

7, the application of high-dissolvability berberine in the medicine of preparation auxiliary curing or pre-preventing tumor and cancer.

8, according to claim 1～7 described application of each claim is characterized in that: described high-dissolvability berberine refers to the various berberines that can dissolve in less than 500 parts of water---comprising citric acid berberine, Berberine bisulfate, phosphoric acid berberine or now be the berberine sulphate of veterinary drug or reagent.

9, application according to claim 8 is characterized in that: described berberine comprises from plant and to extract or berberine that chemical synthesis obtains.

10, application according to claim 8 is characterized in that: described medicine is oral formulations, comprises capsule, tablet, pill, dripping pill, nanometer, micro-capsule, electuary.