GB2271059A

GB2271059A - Pharmaceutical compositions comprising aconitane derivatives

Info

Publication number: GB2271059A
Application number: GB9319500A
Authority: GB
Inventors: Yueqian Qu; Peng Qu; Ming Qu
Original assignee: Individual
Current assignee: Individual
Priority date: 1992-09-23
Filing date: 1993-09-21
Publication date: 1994-04-06
Anticipated expiration: 2013-09-21
Also published as: GB9319500D0; GB2271059B; CN1087516A; CN1042895C

Abstract

A pharmaceutical composition for treating drug withdrawal syndrome and detoxifying addicts comprises an aconitane derivative of formula I/II or their inorganic acid salts or their mixture, or tetrahydroprotaberine derivatives of formula III, with or without anticholinergic agent and a conventional excipient in the pharmaceutical field. The pharmaceutical composition of the present invention is characterized by no drug-dependence, excellent effect, fast action and low side effect. <IMAGE> In the formula I, R= OCH3, OH or OCH3, R1=OAcABz, OH, OABz or H, R2=H or OH, R3=H or OH, R4=H or OH, R5=H or OH, R6=OCH3, OBz, OAc or OH. <IMAGE> In the formula II, R1=R2=R3 OH. In the formula III, R1=OCH3 or OH, R2=OCH3, R3=OCH3 or H, R4=OCH3 or OH, R5=H or OCH3, R6=H or CH3.

Description

Pharmaceutical Composition This invention relates to a pharmaceutical composition containing the aconitane derivatives and the tetrahydroprotoberberine derivatives.

The term "dependence" in this invention refers to a physical (physiologic) or psychological (psycologic) status of interaction of drug and body, which shows abuse of a drug without any treating purpose, to achieve the desired effect, or to avoid the withdrawal symptoms when the drugs were discontinued or reduced used in amount.

The term "withdrawal syndrome" in this invention refers to the patients who depend on the the use of drugs by continuous use, and when stoping the use of the drugs, a series of symptoms such as perspiration, lacrimation, yawing, chilling, getting goose flesh, mydriasis, vomiting, diarrhea, abdominalgia, arrbythmia, blood pressure increase, insomnia, furor, tremor and delirium, etc. wffl happen.

It is reported that there are 50 million drug addicts in the world, and the total volume of drug trade is estimated about US5, 00 billion per year. On one hand, drug abuse results in serious damage to human psyche and body, such as the lose of moral integrity, decrease of health level, life shortening, serious withdrawal syndrome after discontinuing drugs, sometimes even endangering life; on the other hand, drug abuse results in social unstability because the drug addicts always act unscrupulously to get drugs and thereof become a main source of serious crimes in the world. Consequently, the drug abuse has seriously imperiled the progress and safety of the human being. To fight against the worser is drug abuse, goverments all over the world take narsh measures to strictly prohibit drug abuse. However, this problem is getting worseing.Therefore, it is very urgent for the world to invent a medication and method with better cure effect and low side effects in order to control and treat drug addiction.

At present, there are three major methods of treatment for addiction in most countries as the follows 1. Gradually Reducing Regimen The main ingredient of the medication used in the method is opium. Opium content is decreased gradually at the different stage of the treatment until zero.

2. Substitution Method Analgsis methadone is used to treat the drug addict in this method.

3. The Other Drugs Therapy There are also some medications used to treat drug addiction, such as, Buprenorphine, Clonidine, Cydazocine, Dihydroetorphine hydrochloride, etc. However, some of these medications can easily cause nervous derangement and agitation, others will cause the withdrawal syndrome or appear the syndrome because of stopping administrating them.

Clinic practice shows that there are very serious drawbacks in the above three treatments for drug addiction. For example, gradually reducing regimen requires long period of treatment. Furthermore, this method can not made drug addicts foundamentally get rid of this dependency upon drugs, and the propotion of re-abusing after treatment still is high. In substitution method, methadone is an analgetic, and may also result in drug dependence, for example, dependence potential of 100mg of oral methadone is equivalent to that of 10mg of injective morhpine. Meanwhile, methadone itself has many side effects such as pneumonectasis, immunologic symptoms, impotency, as well as accumulation in body leading to intoxication, more seriously, blindness in both eyes. Infants born by mothers addicted methadone are likely to show withdrawal symptoms.In the other drug therapy above, the medications have more adverse side effects and some of them may cause drug dependence.

At present, there are also some medications being tested to treat drug addiction, such as: Abbott 69024, Amantidine, Bupropion, Buprenorphine, Bromocriptine, Buspirone, Carbamazepine (Tegretol), Fluoxetine (Prozac), Flupenthixol, Gepirone, Laam, Mazindol, Naltrexone and Schering 23390 (see ref: Scientific American, March 1991, pp71-79).

Few of them have been provea totally effective and others are being under developing. Thus, there is an urgent need of drug independence medication having high curative effects and low side effects from treatment of drug addiction.

The object of this invention is to provide a pharmaceutical composition to treat drug addiction and a treatment method without drug dependence and with high curative effects and low side effects.

After abroad investigation, the inventor has unexpected found that a pharmaceutical composition containing the aconitane derivatives which have the structures of formula I or II, or their inoganic acid salts, and the tetrahydroprotoberberines which have the sructure of formula III or their inorganic acid salts, possess excellent effects of treatment addiction without drug dependence.

In the formula I, R= OCH3, OH or OCH3, Rl=OAcABz, OH, OABz or H, R2=H or OH, R3=H or OH, R4=H or OH, R5=H or OH, R6=OCH3, OBz, OAc or OH.

In the formula II, R1=R2=Rs=OH.

In the formula III, R1 =OCH3 or OH, R2=OCH3, R3=OCH3 or H, R4 = OCH3 or OH, R5=H or OCH3, R6=H or CH3.

Treating the drug addicts with the pharmaceutical composition of the invention, contained the aconitane derivatives having the structures of formula I and/or II or their inorganic acid salts and the tetrahydroprotoberberine derivatives having the structures of formula III or their inorganic acid salts, can relieve the drug dependence and completly cure withdrawal syndrome within 3-4 days. And pharmaceutical composition possesses drug independence and low side effect. Based on the above discovery, the inventor has completed this invention.

One of the subjects of this invention relates to a pharmaceutical composition which contains the aconitane derivatives having the structures of formula I and/or II or their inorganic acid salts and the tetrahydroprotoberberine derivatives having the structure of formula III or their inorganic acid salts.

In the formula I, R= OCH3, OH or OCH3, R1=OAcABz, OH, OABz or H, R2=H or OH, R3=H or OH, R4=H or OH, Rs=H or OH, R6=OCH3, OBz, OAc or OH.

In the formula II, R1=R2=R3=OH.

In the formula III, R1=OCH3 or OH, R2=OCH3, R3=OCH3 or H, R4= OCH3 or OH, Rs=H or OCH3, R6=H or CH3.

This pharmaceutical componsition can relieve the drug addicts of dependence upon drugs, and treat the withdrawal syndrome resulted from discontinuingly using the drugs. And it possesses no drug dependence and low side effects.

According to this invention, the pharmaceutical composition may contain or may not contain anticholinergic agents such as scopolamine hydrobromide, anisodamine hydrobromide, etc.

According to this invention, the aconitane derivatives having the structures of formula I and/or II are listed in Table 1 and 2, while the tetrahydroprotoberberine derivatives having the structure of formula III are listed in Table 3.

More precisely, the pharmaceutical composition of this invention, contain the aconitane derivatives having the structure of formula I and/or II or their inorganic acid salts and the tetrahydroprotoberberine derivatives having the structure of formula m, contain or not contain anticholinergic agents, as well as pharmaceutically acceptable excipient.According to this invention, the preferred aconitance derivatives having the structure of formula I and/or II or their inorganic acid salts are preferably selected from lappaconitine hydrobromide, lappaconine hydrobromide, N - deacetyl - lappaconitine hydrobromide, the total alkaloids of Aconitum sinomotanum Nakai; the preferred tetrahydroprotoberberine derivatives having the structure of formula III or their inorganic acid salts are the 1-tetrahydropalmatine, dltetrahydropalmatine sulfate, and stephoridine hydrobromide; the preferred anticholinergic agents are scopolamine hydrobromide and anisodamine hydrobromide.

According to this invention, the pharmaceutical composition of the present invention may also contains anticholinergic agents. The pharmaceutical composition of this invention should be preferably selectd from the following formulation: 1. The formulation including lappaconitine hydrobromide and 1 - tetrahydropalmatine or dl tetrahydropalmatine sulfate or stephoridine hydrobromide, with or without scopolamine hydrobromide and/or anisodamine hydrobromide as well as a conventional excipient in the pharmaceutical field.

2. The formulation consisting of lappaconine and 1-tetrahydropaimatine or dl- tetrahydropalmatine sulfate or stephoridine hydrobromide, with or without scopolamine hydrobromide and/or anisodamine hydrobromide as well as a conventional excipient in the pharmaceutical field.

3. The formulation including N - deacetyllappaconitine hydrobromide and 1 tetrahydropalmatine or dl - tetrahydropalmatine sulfate or stephoridine hydrobromide, with or without scopolamine hydrobromide and/or anisodamine hydrobromide as well as a conventional excipient in the pharmaceutical field.

4. The formulation including the total alkaloid hydrobromides of A.

sinomontanum and 1 - tetrahydropalmatine or dl - tetrahydropalmatine sulfate or stephoridine hydrobromide, with or without scopolamine hydrobromide and/or anisodamine hydrobromide as well as a conventional excipient in the pharmaceutical field.

According to this invention, a pharmaceutical composition of this invention can be used in form of tablet, powder, capsule or injection. The form of tablet or capsule is preferred.

The present invention also relates to the use of any of the above compositions or formulations in the preparation of a medicament for treatment of a drug addict.

The other subject of this invention provides a method of treatment of drug - addicts withdrawal syndrome and detoxification of drug addict, which the comprises administrating the pharmaceutical composition of this invention to the drug addicts.

The administration route of the inventive composition can be oral, subcutaneous injection, intramuscular injection, intravenous instillation, etc. The oral administration is preferred. In the treatment of this invention, the administration route is usually oral, the scope of the dosage for oral administration is generally 0.05 0.25mg/Kg/per time of aconitane derivatives of formula I or II or their inorganic acid salts, 12.5mg/Kg/per time of tetrahydroprotoberberine or its inorganic acid salt, 0.00033- 0.OOSmg/KG/per time of scopolamine hydrobromide, and/or 0.066-0. l6mg/Kg/per time of anisodamine hydrobromide.

Generally, oral administration is applied during the first four days, the inventive composition is given every 6 hours, 4 times a day, 2 tablets or 2 pills per time; during the following three days, the composition is given every 8 hours, 3 times a day, 2 tablets or pills per time.

This invention can be further demenstrated by the following experiments, which does not mean, however, any limitation to this invention.

1. Addiction Test of Lappaconitine Hydrobromide 1. 1 Mouse Jumping Test Male mice weighting 18 22g were used for the test and divided into 3 groups (10 for every group). The first group of mice was given a subcutaneous injection in a dose of 80mg/Kg morphine hydrochloride every day and the injection lasted for 20 days. The second group of mice was given a subcutaneous injection of lappaconitine hydrobromide (8mg/Kg), and the injection lasted for 20 days. The third group as control group was given the physiological saline. 6 hours after being given the last dose, all the mice were given intraperitoneal injection of 10mg/Kg allyl dromaran, and then were placed in a cone cylinder cage (diameter=30, height=35). The numbers of jumping for each mouse in 60mins was recorded.The mice of the first group after administrating morphine looked excited, frequently run around and showed obvious pilo - erection reaction. The mice of the group showed obvious jumping reaction after injection of allyl dromaran. The mice of second group after adminisrating lappaconitine hydrobromide looked quiet and immobile, showed no pilo -- erection reaction. After injection of allyl dromaran they showed no jumping reaction.

In another case, male mice weighting 18-22g were divided into four groups (10 for every group). Two groups of mice were injected subcutaneously with lappaconitine hydrobromide 7 times within 2 days. The intial dosage was 3. Smg/Kg. Then, an additional dose of 0. 5mg/Kg and 1. Omg/Kg was escalated for every injection in each group respectively. The third group of mice wasinjected subcutaneously with morphine hydrochloride 7 times within 2 days. The initial dosage was 2. Smg/Kg and an escalating dose schedule (5, 10, 20, 30, 40, 50 mg/Kg) was applied. The fourth group of mice as control group was given the physiological saline. 2 hours after the last injection, all the mice of the above four groups were injected 5 Omg/Kg nalorphine through intraperitoneal cavity.The numbers of jumping within 10 minutes in each group of mice were recorded. The obtained data was summaried in Tab. 4.

The test result in Tab. 4 showes that lappaconitine hydrobromide obviously differs from morphine hydrochloride, and the former does not cause drug dependence.

2. Substitution Test on Weight Reducing of Morphine--dependent rats.

Wister male rats weighting 200--250g were divided into 3 groups (10 for each group). All the three groups were given subcutaneous injection of 25mg/Kg morphine hydrochloride twice a day. The injection lasted for 12 weeks to cause rats dependent upon morphine. After discontinued injection of morphine, the rats showed suppressive and immobile, refusing food and losing weight (after 24 hours, the rats lost weight averagelly of 25g). Then the three groups of rats were injected morphine, lappaconitine and physiological saline, respectively.The weight changes of the rats were observed and recorded in Fig. 1 Notes for Fig. 1: Abscissa - -time (hr): 24hr after stopping injection of morphine for three groups of rats, and injected subcutaneously with morphine, lappaconitine and physiological saline, respectively, the average weight change of the rats within 8hr in each group were recorded. The 24th hour after stopping injection of morphine is proposed to be zero.

Ordinate- - weight of rats: The average weight lost of the three groups of rats at the 24th hour after stopping the injection of morphine, and the average weight change in 8hr in each group after 24 hours of injection of morphine, after the rates were given injection of morhpine, phisiological saline and lappaconitine, respectively. In the test, the average weight before stopping injection of morphine is proposed to be zero.

I: Morphine hydrochloride 25 mg/Kg. sc II: Physiological saline 2ml/Kg. sc m Lappaconitine hydrobromide 8mg/Kg. sc Figure 1 showed that the group of rats which were injected morphine looked turning to excited from being suppressive, moved increasingly, frequently taking food and water, and the weight increased to the level before stopping injection of morphine very quickly. Figure 1 also showed that the group of rats which were injected lappaconitine still looked suppressive and-no weight increase was observed. The test results indicated that lappaconitine did not act as a substitution for morphine.

3. Monkey addiction test Three of the 6 Macaca mulatta weighting 2. 75 - 4. 75Kg were subcutaneously injected lappaconitine twice a day. The initial dosage is 0O lmg/Kg, the dose was successively escalated to the maximum tolerance dosage, 2mg/Kg within 50 days. Then, the tolerance dosage was maintained to the 53rd day, 61th day and 92nd day, respectively. The total injection dosage for the three monkeys were 196, 400 and 635mg, respectively. On the day 63 and the day 92, the injection of lappaconitine to the monkeys was stopped. During the following 24 hours, the monkeys had no different behavious and appetite from that before stopping injection. On the day 29, 53, 59, 67 and 90, injection to the monkeys were discontinued and after 18 hours subcutaneous injection of nalorphine (4 or 8 mg/Kg). No withdrawal symptoms was observed.Another three monkeys were given subcutaneous injection of morphine twice a day. The initial dosage was 2. 5mg/Kg, and dosage was successively increased to 25mg/Kg on the day 21. Then, this disage was maintained until the 30th day, and the monkeys showed dependence on morphine. After 18 hours stopping injection of morphine, the monkeys showed obvious withdrawal syndrome such as agitation and restlessness, turning, lying on side or in the bottom of cage time to time, scratching, biting chain, crying, vomiting, shivering, paroxysmal tremol, etc. At that time, if a subcutaneous injection of nalorphine was given to the monkeys, the above symptoms would be more obvious. After subcutaneous injection of morphine to the monkeys, the above withdrawal symptoms become obviously reduced or disappeared in 3~5 minutes.A subcutaneous injection of 2mg/Kg lappaconitine could not relieve or weaken the above withdrawal symptoms. This indicates that lappaconitine has no action of substitution for morphine. The above test results were shown in Tab. 5.

The above test results indicates that lappaconitine, different from morphine, does not cause dependence after long term use.

II. Toxicity Test II. 1 Acute Toxicity Test Healthy mice weighting 18-22g were given toxicity dosage of lappaconitine through in gasteria, subcutaneous injection and intravenous injection, and then showed toxicity reaction such as paroxysmal restlessness, foreleg keeping tic. While given lethal dosage, the mice showed paroxysmal convulsion, respiration suppression until suffocation, death. The LD50 values (95 confidence limit) for, in gasteria, subcutaneous injection and intravenous injection were 32. 4 (25. 9-40. 5), 11. 7(9. 2-14. 9) and 8. 4(7. 2-9.

7) mg/Kg, respectively. After being given intraperitoneal injection of toxicity dosage of lappaconitine, rats looked suppresive and immobile lying on stomach in cage, obvious suppression of respiration and showed convulsions before death. The Lid50 for lappaconitine was 16. 5(15. 0-18.

l)mg/Kg.

Two Macca Mulatta were given subcutaneous injection of 2mg/Kg lappaconitine. No toxic reaction and no effect on electrocardiography were observed. 30 minutes after being given subcutaneous injection of 3mg/Kg lappaconitine, the monkeys showed restlessness, slobbering, swallow increasing, eyelids drooping, rigidity of legs muscle. After 45 minutes, one monkey increased restlessness, further developed convulsion. During convulsion its respiration stopped, and recovered with artificial respiration, but still existed convulsion until death after 1 hr. Another monkey didnot give sign of convulsion, and the above toxic reaction lasted for 2 hours and then disappeared. Electrocardiography examination indicated that T wave had elevation, T wave and P wave fused, and R wave become smaller and notching. Next day, the electrocardiography examination indicated that the monkey was normal.

II. 2 Subacute toxicity Test Ten Wister rats weighting 200--250g were divided into 2 groups (5 for each group). Each group was given intraperitoneal injection of 5mg/Kg or 10mg/ Kg of lappaconitine a day, respectively. The injection was continued for 30 days. 5 wister rats of control group were given subcutaneous injection of saline (2ml/Kg). Compared to the control group, the medicine group of rats were inhibited on weight increase at different levels. No obvious change was observed in electrocardiography examination. No change was observed during the test of hepatic and renal function (GPT, zinc sulfate turbity test, urea nitrogen, creatinine) and histological and pathological examination of different viscera.

Other ten Wister rats were given successively escalated dose, in other words, the rats were first injected lappaconitine (8mg/Kg) intraperitoneally, after one week, 10mg/Kg; after 2 weeks, 12mg/Kg; after 16 days, 14 mg/Kg; and the last dose was maintained until the day 28. The test results indicated that the weight increase of the medicine group of rats got a little suppression, compared to the control group. The histological and pathological examination of all viscera indicated similar results to the control group, except a little myocardial edema and hydropic degeneration.

Three Macca Mulatta weighting 2. 75 4. 75Kg were injected lappaconitine subcutaneously twice a day. Initiated with 0. lmg/Kg, the dosage was increased successively to the highest tolerance dosage, 2mg/Kg within 50 days, and the last dosage was maintained to the day 53, day 67 and day 92, respectively. The accumulated injective dosage was 196, 400 and 635 mg, respectively. No toxic reaction for monkeys was observed during the administration process. No obvious change appeared during the continuous elctrocardiographic examination. Histological and pathological examinations mainly indicated stimulating reaction, except a little edema and hydrodenaturation in liver and increasing cerebral colloid cells.

III. A Treatment Test For Mice Dependent on Morphine or cocaine Male mice weighting 18- 22g (5 groups of 10 mice each) were injected subcutaneously morphine (100mg/Kg) twice a day, and the injection was continued for 8 days. 6 hours after the last dose, mice were injected nalorphine (50 mg/Kg), and then, the mice showed frequent movement, attacking reaction and jumping reaction. The jumping reaction was most vigorous within the first 30 minutes. Based on the jumping reaction of the mice, those mice morphine-dependent, whose jumping number within 30 minutes was more than 60% of the average jumping number, were selected and divided at random into 8 groups of 10 mice each.

A seven - day treatment to relieve morphine - dependence was conducted based on the medications, the dose and administration route listed in table 6 for each group of mice which produce morphine-dependence. Wherein the first 4 days, administration was made once per 6 hours, four times a day.

From the day 5 through the day 7, administration was made up once per 8 hours, three times a day. On the day 5 and the day 8 of treatment, subcutaneous injection of nalorphine (50mg/Kg) was made respectively to induce addiction. The test results indioated that each group of mice gave negative reaction against nalorphine except the control group of morphine dependent mice most of which died during seven days of subcutaneous injection of saline. During the following 3-day observation after stopping the treatments, the mice treated did not appear withdrawal symptoms. Even nalorphine (50mg/Kg) was injected subcutaneously, the mice did not appear withdrawal symptoms either. The results were listed in Tab. 6.

In the same way as described above, subcutaneous injection of cocaine (1 Omg/Kg) was made to the mice twice a day, and the injection was continued for 7 days. During this period of injection of cocaine, mice gave abnormal signs such as anorexia, pilo - erection, and frequent walk with holding tail, etc. After treatment with lappaconitine, the mice recovered to be normal.

IV. Clinic Treatment Test Case 1 A 29- year - old male addict has taken heroine for about 4 years. The pharmaceutical composition of medications of this invention were administrated to him before he appeared withdrawal symptoms. In the first day after administration, the addict didn't appear other withdrawal symptoms except intermittent perspiration. In the second day of treat meat, the addict appeared withdrawal symptoms such as light perspiration, yawing, lacrimation, mydriasis, etc., as well as once vomiturition and once diarrhoea, except light * elbowache lasted intermittently about 16 lrrs. and somewhat serious * * palpitation lasted intermittently about 4 hrs.

However, the addict had normal sleep and diet The above withdrawal symptoms disappeared in the evening of the second day and did not reappeared. He is cured.

Case 2 A 27- year - old male addict had taken heroine for about 6 years. The pharmaceutical composition of this invention was administrated to him before he was observed to appear withdrawal symptoms. In the first day after administration, the withdrawal symptoms did not appear until the 10 hour after administration of the composition of the day. After 10 hrs, the addict was observed to appear withdrawal symptoms such as light yawing, raving in sleep, mydriasis and etc., as well as once vomiturition, twice abdominal pains and diarrhoeas, except the withdrawal symptoms (lasted 38 hrs) included mainly intermittent light palpitation, ache of shanks and arms, as well as somewhat serious** palpitation lasted intermittently for 5 hrs. But the addict had normal sleep and diet.The above withdrawal symptoms disappeared at the 60th hour after administration, and did not reappeared.

He was cured.

Case 3 A 29- year - old male addict had taken heroine for about 5 years. The pharmaceutical composition of this invention was given to him before he was observed to appear withdrawal symptoms. He was not observed to appear the symptoms within 12 hrs after administration. After 12 hrs, the addict appeared the symptoms such as light palpitation, perspiration, mydriasis and etc., as well as three times vominturition and twice diarrhoea, except light * or somewhat serious * * aches of shanks and waist. The addict had normal sleep and diet. The above withdrawal symptoms disappeared totally and did not reappeared at the 65th hours after administration. He was cured.

The above clinic tests results demonstrated that the pharmaceutical composition of this invention to treat drug addiction does not cause drug dependence. It has good effect to relieve drug dependence, to cure withdrawal symptomes and act rapidly without side effects.

Light * : be marked as +, the manifestations demenstrate palpitation, aches of waist and legs told by addics; lying and sitting; sometimes tossing and tumbling on bed; no pain in addicts face; sometimes having hours sleep. somewhat serious * *: be marked as + +, the manifestations demenstrate: being on pins and wheedles, walking back and forth in the room; or having aches of waist and legs, being on pins and needls, requirement for extending arms and legs, having pain on addits - face.

Serious * * * : be marked as +++, the manifestations demonstrates: having wild behaviour; producing bloody behaviour such as bumping with head, persecution, etc. In the cases of treatment, there were no serious.

But, very few addicts said that they felt unwell as if a insect was crawling within their arms and legs.

Table 1: The relief substances of formula I (their inorganic acid salts included) for dependence - inducing drugs (such as opium morphine, heroine, cocaine, marijuana, amphetamine, etc. ).

No. aconitane derivatives Formula MW mp ( C) 1 Lappaconitine C32H44N2O8 584 224-225 2 Lappacomine C23H37NO6 423 78-80 3 N-Deacetyllappaconitine C30H42N2O7 542 117-119 4 Isolappaconitine C32H44N2O@ 584 198-200 5 Deoxylappaconitine C32H44N2O7 568 212-214 6 Neofinaconitine C30H42N2O6 526 7 Ranaconitine C32H44N2O9 600 130-131 8 Ranaconine C23H37NO7 439 105-107 9 N-Deacetylranaconitine C30H42N2O8 558 125-127 10 Finaconitine C32H44N2O10 616 220-221 11 N-Deacetylfinaconitine C30H42N2O9 574 121-123 12 Puberanine C32H44N2O0 600 13 piscopalisine C29H39NO6 497 14 Episcopalisinine C22HssN0s 393 152-154 15 Episcopalitine C24H37NO5 419 16 Delavaconitine C29H39NO6 497 17 Delavaconine C22H35NO5 393 152 18 Aconosine C22H35NO4 377 142-143 19 Scopaline C21H33NO4 363 167-169 Table 1 (continued)

No. aconitane derivatives Specific Rotation R1 R2 1 Lappaconitine [α]D25 27.0 (C0.22, CHCl3) OAcABz H 2 Lappaconine OH H 3 N-Deacetyllappaconitine [α]D33 39.9 (C1.5, CHCl3) OABz H 4 Isolappaconitine @ OAcABz OH 5 Deoxylappaconitine OAcABz H 6 Neofinaconitine OABz H 7 Ranaconitine # Ca)2D 40. 2 (CO. l9,MeOH) OAcABz OH 8 Ranaconine OH # OH 9 N-Deacetylranaconitine [α]D26 43.7 (C2.0, CHCl3) OABz OH 10 Finaconitine [α]D22 44.7 (C0.1., Me OH) OAcABz OH 11 N-Deacetylfinaconitine [α]D1 34.9 (C0.46, CHCl3) OABz OH 12 Puberanine [α]D20 16.6 (C0.6, CHCl3) OAcABz OH 13 Episcopalisine [α;]D21-11.7 (C3.2, EtOH) H H 14 Episcopalisinine [α]D26-8. 7 (C6. 8, EtOH) H H 15 Episcopalitine [α]D22-0.90 (C14.0, EtOH) H H 16 Delavaconitine [α]D22-25.

17 Delavaconine [a]# - 6. 4 (Cl. 23, CHCl3) H H 18 Aconosine [a]# - 25. 40(C4,Me OH) H H 19 Scopaline H H

Table 1 (continued).

No. R R4 R5 R6 R Original Plant 1 OH H H OCH3 αOCH3 A conitum sinomontanum Nakai; A. finetianum Hand-Mazz 2 OH H H OCH3 αOCH4 3 OH H H OCH3 αOCH3 A. finetianum Hand-Mazz 4 H H H OCH3 αOCH3 A. finetianum Hand-Mazz 5 H H H OCH3 aOCH3 A. finetianum Hand-Mazz 6 H H H OCH3 aOCH3 A. finetianum Hand-Mazz 7 OH H H OCH3 αOCH3 A. conitum sinomontanum Nakais A. finetianum Hand-Mazz 8 OH H H OCH3 αOCH3 9 OH H H OCH3 αOCH3 A. finetianum Hand-Mazz 10 OH OH H OCH3 αOCH3 A. finetianum Hand-Mazz 11 OH OH H OCH3 αOCH3 A. finetianum Hand-Mazz 12 OH H H OCH3 # ssOCH3 A. barbatum var. puberulum 13 OH H H OB, aOCH3 A. episcopa Le'vl 14 OH H H OH αOCH3 A. episcapale Le'vl 15 H H H OAc αOCH3 A. episcopale Le'vl 16 H H OH OBz αOCH3 A. delavayi Franch 17 H H OH OH αOCH3 18 H H H OH aOCH3 A. forestii Diels 19 H H H OH aOH A. episeopalo Le'vl

Table 2: The rilief substance of formula Il (it inorganic acid salt) for dependence-inducing drugs (such as opium, morphine, heroine, cocaine, marijuana, amphetamine, etc. ).

Name formula MW mp ( C) Specific R1 R2 R3 Original Rotation Plant Aconine C25H41NO9 499 132 [α]p+23 OH OH OH

Table 3-1 The relief substances of formula m ( their inorganic acid salts included) for depence-inducing drugs (such as opium, morphine, heroine, cocaine, marijuana, amphetamine, etc. )

tetrahydro No. protoberberine formula MW mp ( C) Specific Rotation R1 derivatives 1 l-tetrahydropal C21H25NO4 355 144 [αD26 - 295 (C=0.8, EtOH) OCH3 -matine 2 dl-tetrahydropal C21H25NO4 355 148-149 [α]0 D OCH3 -matine 3 Stephoridine C19H21NO4 327 129-133 [α]D21 - 263 (C=0.337, MeOH) OH 4 Corydaline C22H27NO4 369 135 [α ;]D20 +211 (C=0.8, etOH) OCH3 5 Xilopinine C21H25NO4 355 181-182 [α]D15 -177.2 (C=4.07, CHCl3) OCH3 Table 3-2

No. R2 R3 R4 R5 R6 Original plant I OCH OCHa O OCH3 H H Stephania viridiflavens H. s. Lo et M. yang.

S. kwangsiensis H. S. Lo S. rotunda Lour.

S. sinica Diels Corydalis pallida (thumb) Pers.

2 OCH3 OCH3 OCH3 H H C. yanhusuo W.T. Wang C. decumbens (thunb. ) Pers.

C. racemosa (thunb.) Pers.

3 OCH, OCHs OH H H Menispermum dauricum DC Menispermum dauricum DC.

Menispermum dauricum DC.

4 OCH3 OCH3 OCH3 H CH3 C. ambigua Chem. et Schlecht var. amurensis Maxim.

C. Koidzumiana Ohwi C. marschalliana Pers.

5 OCH3 H OCH3 OCH3 H Xylonia discreta (Lifil.) ) Sprague et Hutchins.

Xylonla discreta (Lifil. ) Sprague et Hutchins.

Table 4. Observation of jumping reaction for mice after subcutaneous injections of lappaconitine or morphine Number of mice riven Dosage admini- Accumu- Given Tested pharmaceu- (mg/kg) stration* lated pharmaticals (day) Total Dosage ceuticals (mg/kg) Physiological - 2 10 10 saline - 20 10 10 Morphine 2.5 2 157.5 10 10 80 20 1600 10 10 Lappaconitine 3.5 2 35 10 10 3.5 2 45.5 10 8.0 20 160 18 18 Table A (continued) mg/kg ip number of jumping Given Nalorphine allyl-dromaran -jumping mice times of pharmaceuticals each mouse Physiological 50 0 0 saline 10 0 0 Morphine 50 7 9 10 9 34 Lappaco- 50 0 0 nitine 50 0 0 10 1 0.2 * Once a day for 20 days group; Five times of injection on first day and twice on second day for 2 days group.

** During the administra-.tion of pharmaceuticals, five mice died of accumulated toxicity.

Table 5 Observation of the substitution role of lappaconitine in the withdrawal syndrome of morphine-dependent monkeys No. of Injection accumulated Withdrawal Syndrome lappaconitine monkey morphine total dosage 18 hr after Nalorphine (2mg/ kg sc) (day) (g) stopping 0. 5 mg/kg morphine Sc 6 42 4.66 + 7 40 3.56 + 62 6.59 + 69 7.56 + 91 10.97 + 8 33 3.61 + 49 6.06 + Table 6 Observation of treatment for Mophine-dependent Mice Days of Accumulated Number of Mice Dosage Administration Total Dosage Morphie- Treatment Medication mg/kg (time/hours) (mg/kg) dependent (Administration the Day the Day route) 1-4 5-7 Saline 10 rnl/kg 1/6 1/8 250ml 10 8 (sc) Lappaconitine 0.45 1/6 1/8 11.25 10 10 hydrobromide (sc) Lappaconitine 0.225 1/6 1/8 5.63 10 10 hydrobromide # (sc) Scopolamine 0.05) hydrobromide (sc) Lappaconitine 0.45 1/6 1/8 11.2 10 10 hydrobromide Scopolamine 0.1 2.5 hydrobromide (sc) Lappaconitin 0.9 1/6 1/8 22.5 10 10 hydrobromide Scopolamine 0.2 5.0 hydrobemide (ig) Lappaconitine 0.45 11. 25 hydrobromide 0.1 1/6 1/8 2.5 10 10 Scopolamine (ig) hydrobromide N-deacetyllapp- 5 1/6 1/8 125 10 10 aconitine (sc) hydrob romide Lappaconine 5. 1/6 1/8 125 10 10 hydrobromide (sc) Table 6 (continued) Nalorphine Number of Jumping Mice (Nos. of Jumping Mice/Nos. of Survived Mice) the Day 5 the Day 1 the Day 4 Medication mg/kg of treatment of stopping of stopping drug administration Saline 50 4/6** 3/3** Lappaconitine 50 1/10* 0/19 0/10 hydrobromide Lappaconitine 50 1/10*4 1/10* 1/10* hydrobromide, Scopolamine hydrob romide Lappaconitine hydrobromide, Scopolamine 50 0/10 0/9 0/9 hydrobromide Lappaconitine hydrobromide, 50 0/10 0/8 0/8 Scopalamine hydrobromide Lappaconitine hydrobromide, 50 1/10 *5 0/9 0/9 Scopolamine hydrobromide N-deacetyllappaconitine 50 0/10 0/10 0/10 hydrobromide Lappaconine hydrobromide 50 0/10 0/10 0/10 Note: * denotes a clinic prescription, but scp is larger than clinic prescription.

* * 4/6 denotes: six mice are survived, the four therein have ability of jumping and the jumping times of the four is 17, 14, 8 and 16 respectively; 3/3 represents that there are three mice being survived, and the jupming times of the three are 12, 10 and 9 respectively; 1/2 denotes that there are two mice being survived, and the one therein has ability of jumping 7 times.

* 3 denotes that ten mice were survived during the test, but only one therein jumped five times.

*4 denotes that ten mice are survived during test, only one therein jumped 10, 6 and I times respectively on the fifth day of treatment, the eighth day of treatment and the fourth day of stopping administration.

* 5 denotes that ten mice were survived during the test, only one therein jumped 16 times.

Claims

1. A pharmaceutical composition to treat drug addicts withdrawal syndrome and to detoxify them, including the aconitane derivatives having the structure of formula I/II or their inorganic acid salts or their mixtures, and the tetrahydroprotaberberine derivatives having the structure of formula III, with or without anticholinergic agent and a conventional excipient in the pharmaceutical field,

where; in the formula I, R= OCH3, OH or OCH3, R1=OAcABz, OH, OABz or H, R2=H or OH, R3=H or OH, R4=H or OH, R5=H or OH, R6=OCH3, OBz, OAcOH or OCH3, R1=OAcABz, OH, OABz or H, R2 =H or OH, R3=H or OH, R4=H or OH, R5=H or OH, R6=OCH3, OBz, OAc or OH,

in the formula II, R1=R2=R3=OH in the formula III, R1=OCH3 or OH, R2=OCH3, R3=OCH3 or H, R4= OCH3 or H, R5=H or OCH3, R6=H or CH3.

2. The composition of claim 1, in which the said aconitane derivatives are lappaconitine or its inorganic acid salts.

3. The composition of claim 1, in which the said aconitane derivatives are N -deacetyllappaconitine or its inorganic acid salts.

4. The composition of claim 1, in which the said aconitane derivatives are lappaconine or its inorganic acid salts.

5. The composition of claim 1, in which the said aconitane derivatives are aconine or its inorganic acid salts.

6. The composition of claim 1, in which the said aconitane derivatives are the total alkaloids of Aconitum suromontanum Nakai or its inorganic acid salts.

7. The composition of claim 1, in which said tetrahydroprotoberberine derivative is 1-tetrahydropalmatine.

8. The composition of claim 1, in which said tetrahydroprotoberberine derivative is dl -tetrahydropalmatine.

9. The composition of claim 1, in which said tetrahydroprotoberberine derivative is stephoridine.

10. The composition of claim 1, in which said tetrahydroprotoberberine derivative is corydaline.

11. The composition of claim 1 of which the said tetrahydroprotoberberine derivative is xilopinine.

12. The composition of claim 1, in which said anticholinergic agent is selected from scoplamine hydrobromide and anisodamine hydrobromide.