JPS5810518A - Remedy for alcoholism or sedative and hypnotic addiction - Google Patents

Abstract

PURPOSE:To prepare the titled remedy containing pindolol as an active component and exhibiting no drug dependence, cross tolerance and cross dependence. CONSTITUTION:The titled remedy is prepared by using pindolol which is a beta- blocker used as an remedy for hypertension and arrhythmia, as an active component, and forming in the form of tablet or injection. The carriers usable in the preparation of the tablet are diluent (e.g. lactose, starch, etc.), binder (starch, gelatin, etc.), disintegrant (e.g. starch, agar, etc.), and lubricant (e.g. magnesium stearate, talc, etc.). Dose: 30mg of pindolol daily by oral administration.

Description

[Detailed Description of the Invention] Unexploited EA relates to a therapeutic agent for alcoholism or sedative-hypnotic addiction containing pindolol as an active ingredient. Conventionally, benzodiazepine derivatives, Namely, diazepam (DZP) and nitrazepam (N
ZP) is widely used.

However, since diazepam has cross-tolerance and cross-dependence with these sedative-hypnotics, withdrawal symptoms due to diazepam withdrawal occur after recovery from the addiction caused by the sedative-hypnotics. Not only that, after addicted patients are discharged from the hospital, diazepam preference is high at 19° and a tendency to abuse appears.

Accordingly, one object of the present invention is to provide a sedative-hypnotic therapeutic agent that does not have the above-mentioned disadvantages.

The inventors of the present invention have conducted intensive studies to develop a complete range of sedative-hypnotic addiction treatment drugs that do not have cross-tolerance or cross-dependence.
The β-blocker pindolol, which is conventionally used clinically as a drug for hypertension and arrhythmia, surprisingly inhibits sedative-hypnotic withdrawal symptoms such as barbital withdrawal convulsions, irritability, general muscle stiffness, and motor coordination disorder. If the drug is addictive, does it not show cross-tolerance and cross-dependence like diazepam does? I found it.

We investigated the effects of pindolol on sedative-hypnotic withdrawal symptoms through pharmacological tests. The study was to measure the inhibitory effects of pindolol on the preconvulsive symptoms and clonic-tonic convulsions induced by the application of the monoamine oxidation inhibitor tranylcyglomine (CTcp) during withdrawal of valpital. [811 heads Eijibu et al.: No. 5]
Abstracts of the 4th Annual Meeting of the Japanese Pharmacological Society (Fukuoka), 120 pages (
1981)] 0 Appearance et al.'s method [Appearance Eijibe et al.: Psychophar
Macology.

57, pp. 137-144 (1978)], Sprague-Dawley male rats (body weight 100 to I20F) maintained at s-+4 under constant temperature and humidity were subjected to the following procedures. Total parbital dependence was acquired by sequentially feeding feed #+: barbital (BJ O, 5 and 1 wf/V mixed feed to 4
Bl and 2wg/f mixed feed $+ for 6 days.

Feed mixed with B2 and 4~/ for 6 days, B4 and 6my/
Contamination of V @ 10 days of restaurant, and contamination of B6 and 8■/2! @ Department for 10 days. After the final application of barbital, the barbital-containing feed was replaced with normal feed, and the appropriate drug was administered at 48:00.
5 in each group at the time when the onset of severe drug-appropriate symptoms persists.
Five groups of ~6 rats were given pindolol alone (3
■/Kf or lO Cape/Kf, administered intraperitoneally) A combination of pindolol (3~/Kg or 10 m1P/su, administered intraperitoneally) and diazepam (5'q/Kf, orally) is administered. In the control group, pindolol was not administered, and physiological saline was administered intracavitally instead.Tranylthyglomine 2011FZ- was intraperitoneally administered 30 minutes after each drug administration.Tranylthyglomine was then administered intraperitoneally. After administration, the time (T+) for onset of convulsive symptoms (kangaru uniform posture or forelimb twitching), &
Clonic symptoms after full administration of tranylcypheromin to paralyzed patients.
The time at 1 (Ty) for onset of severe convulsions was measured. General symptoms were observed for 30 minutes after administration of tranylcybromine, and the mortality rate due to Tcp-induced convulsions within 6 hours was calculated. <'4 The results are shown in Table 1 below.

,゛, Toyo E2 As shown in Table 1 above, when tranylcypcumin 2011F/odor was administered to the control group, 8 to 9 minutes after administration.
Severe clonic-tonic convulsions, mostly on the lateral side, developed from 0 to 100%. -10,000, Pintoor 3"F/4 and 10M9/Kgt pretreatment-j,l:) The intensity of ranylcypromine-induced convulsions was significantly reduced, and the incidence of convulsions was also significantly suppressed (suppression rates are 67% and 83% respectively),
A dose-related suppressive effect on clonic-tonic convulsions was observed with pindolol. The mortality rate within 6 hours after administration of tranylcypromino was also significantly reduced [without pindolol administration: 80%, with pindolol administration: 0-1
7%]. Furthermore, when pindolol was combined with a small amount of diazepam, the anticonvulsant effect was enhanced (the onset of clonic-tonic convulsions was completely suppressed), and the mortality rate within 6 hours after administration of tranylthygromine was increased. was 0%. From Table 1, it can be seen that pindolol has an extremely excellent therapeutic effect on symptoms and symptoms of palpyrate.

For comparison, pharmacological data on the conventionally known pharmacological effects of pindolol, ie, antihypertensive and antiarrhythmic effects, are described below.

Pindolol 1519/day was orally administered to 15 patients with essential hypertension for 8 weeks to confirm its usefulness as an antihypertensive agent. Its antihypertensive effect was significant after 2 weeks, and after 8
Opening 1 showed a stable hypotensive purple color. Although there was a significant decrease in pulse rate after 6 weeks, the decrease was slight. ([Pharmacology and Therapy J, VOI.

8, No. 3, pp. 207-210, March 1980 issue).

Regarding anti-arrhythmia effects, 20 adult mongrel dogs were given Frozen, laughing gas, oxygen anesthesia 2,
Pindolol 0.0211F/Ill'' was injected intravenously.

With the administration of pindolol, the heart rate showed a mild decrease of 6-9%, and with nolopranolol, it was 16-22%; there was a significant difference between the two, and the change in arterial pressure was 1-22% with pindolol.
Although there was a slight tendency for a decrease of 2%, no significant change was observed overall (1-5% for nolopranolol), and a mild decrease in cardiac output of 9-11% was observed. (14-24% for noropranolol; significant difference between the two).

Arrhythmogenic epinephrine IT was 14 μt/Ky on average in the pindolol-administered group, and 15 μf/Ky on average in the noropranolol-administered group. From these results,
Pindolol 0.02■/- and Noropranoroll 081
Although it exhibited an antiarrhythmia effect to the same degree as Ki/Kf, its degree of inhibition on the cardiac circulatory system was far superior to that of Pindolol. ("Anesthesia", Volume X■.

No. 10, pages 1134-1135).

The LD5o (·vq/Kf) of pindolol is as follows: W of oral administration to mice, 25% in males.
3.6. 268.7 for females; 35.7 for males when administered intravenously to mice. 38.8 for females: 263.3 for males when administered orally to rats. 269.6 for females;
For intravenous administration to rats, 53.6. In females, it is 51.3.

According to the present invention, there is provided an agent for the treatment of alcoholism I or a sedative and hypnotic drug containing pindolol as an active ingredient. The therapeutic agent according to the present invention is a tablet.

It can be prepared as an injection and administered orally or by subcutaneous or intravenous injection.

In the case of tablets for oral administration, lactose can be used as a carrier for the therapeutic agent according to the present invention.

Excipients such as dengue, sucrose, glucose, microcrystalline cellulose, calcium carbonate or kaolin; binders such as dengue, gelatin or hydroxynorobil cellulose; denone, agar, gelatin, sodium carboxymethyl cellulose or calcium or kaol crystals Disintegrants such as cellulose, as well as; magnesium or calcium stearate, talc, macrogol-4
000 or 6000. Mention may be made of lubricants such as stearic acid.

The therapeutic agent according to the present invention is prepared according to the conventional method in the pharmaceutical industry.
4#! can.

The daily dose (oral administration) for humans of the therapeutic agent for alcoholism or sedative-hypnotic addiction according to the present invention is as follows.

It is about 30 cm as a pin roll.

The treatment agent for alcoholism I or sedative-sedative drug addiction of the present invention (
An example of a prescription for tablets is given below. Composition in one tablet: Pindolol 5.0sF crystalline cellulose 90.0~lactose
20.7111? Hydroxyglobyl cellulose -0,64 Special category: Applicant Kowa Pharmaceutical Co., Ltd. %Fl - Patent attorney representing the applicant Akira Aomizu, patent attorney Kazuyuki Nishidate, 9P attorney Yukio Uchida, patent attorney Akira Yamaguchi

Claims (1)

[Scope of Claims] 1. A therapeutic agent for alcoholism or sedative-hypnotic addiction, comprising pindolol as an active ingredient. 2. The drug consortium for treating alcoholism or sedative-hypnotic drug according to claim 1, which is used to treat all withdrawal symptoms of alcohol, pulpyrates, or tranquilizers.