Clorazepate 및 medazepam이 가토 혈중 주정농도에 미치는 영향에 관한 실험적 연구

Abstract

[한글]

Clorazepate와 modazepam은 비교적 최근에 개발된 benzodiazepine계 유도체들로써 diasepam 및 chlordiazepoxide와 유사한 성상이 있는 항불안제로 임상에 사용되고 있다. 이들은 이들은 항불안 작용만이 비교적 강한 반면 졸음이나 운동실조와 갈은 부작용은 적다고 알려졌지만 clorazepate의 kinetics에 대해서 알려지지 않은 점이 있다. Medazepam은 흡수가 신속하고 대사가 빨라 혈중에서 거의 축적되지 않는 것으로 시사되었다.

한편 정은제의 복용시 주정 섭취로 인한 사고 유발 위험성이 증가하고 있기 때문에 주정과의 상호작용을 알아 보는 것이 중요하다고 주장되고 있다. 이러한 사실에서 clorazepate 및 medazepam이 가토 혈중 주정 농도에 미치는 영향을 규명해 봄은 이론적으로나 실제적으로 의의있는 바로 고려되어 본 연구를 시행하였다.

실험재료 및 실헝방법

1. 실험동물은 2.0kg 내외의 정숙자웅 가토를 사용하였다.

2. 비교군에서는 주정만 단독 투여하였다.

3. 실험군은 주정 + Clorazepate (5mg/kg 연 5일 투여), 주정 + Clorazepate (5mg/kg 연 7일 투여), 주정 + Medazepam (5mg/kg 연 7일 투여), 주정 + Medazepam (5mg/kg 연 10일 투여), 및 주정 + Medasepam (10mg/kg 연 7일 투여)로 6군으로 나눴다.

4. 주정투여는 20% ethanol 용액을 체중 매 kg당 5.0ml를 이변정맥(耳 靜脈)내로 5분간에 걸쳐 서서히 정맥 주사하였다.

5. 체혈은 주정투여후 15분과 45분에 심장 천자로 시행하였다.

6. 주정의 혈중 농도는 Cavett씨 방법에 의해 측정하였다.

실험결과

1. Clorazepate를 5mg/kg씩 연 5일 및 연 7일간 투여시, 또 한 10mg/kg씩 연 7일간 투여시 주정투여후 15분 및 45분에서 각각 혈중 주정농도를 유의하게 높였다.

2. Medazepam을 5mg/kg씩 연 7일간 투여시 주정투여후 15분 및 45분에서 각각 혈중 주정농도에 유의한 변화가 없었으나 5mg/kgTlr 연 10일간 또한 10mg/kg씩 연 7일간 투여시에는 주정투여후 15분 및 45분에서 각각 혈중 주정농도를 유의하게 높였다.

[영문]

Both clorazepate and medazepam are relatively newer anxiolytics of benzodiazepine derivatives; clorazepate is carboxylated form of desmethyldiazepam, and medazepam is benzodiazepine analogue of a 2-ketone omitted. These drugs show characteristic taming effect, muscle relaxant, and anticonvulsant properties with relatively little side effect and these drugs indicate rapid absorption and rapid biotransformation by oral administration, with more rapid onset of action for the former. It is found that desmethyldiazepam is the major metabolite of clorazepate

and medazepam, which is regarded ato be important active substance to produce beneficial effects of these benzodiazepine derivatives in clinical application.

Investigators suggested that any new psychotropic drugs should be tested for its interaction with alcohol, because they might precipitate the risk situation in case of consuming them concurrently.

Recently it has been reported that various psychotropic agents tended to elevate the blood alcohol level.

In view of these reports, the author conducted an animal experiment to investigate the effects of both clorazepate and medazepam on the blood alcohol level in rabbits.

Material and Method

1. The experimental work was done on mature rabbits of both sexes, weighing about 2 kg.

2. The experimental animals were divided into two groups; the control and the experimental group.

3. The control group was given alcohol alone.

4. The experimental group was divided into 6 subgroups;

a) alcohol plus clorazepate, 5mg/kg of body weight for 5 days.

b) alcohol plus clorazepate, 5mg/kg of body weiht for 7 days.

c) alcohol plus clorazepate, 10mg/kg of body weiht for 7 days.

d) alcohol plus medazepam, 5mg/kg of body weiht for 7 days.

e) alcohol plus medazepam, 5mg/kg of body weiht for 10 days.

f) alcohol plus medazepam, 10mg/kg of body weiht for 7 days.

5. Each clorazepate or medazepam was given orally in a single dose at a fixed time. The last dose was given one hour and a half befor alcohol administration.

6. In all groups 20% ethanol solution was slowly given in a dose of 5.0mg/kg of body weight for 5 minutes by intravenous route.

7. All of the blood specimens were obtained by cardiac puncture at both 15 and 45 minutes after alcohol administration.

8. The determination of blood alcohol level was made by Cavett's method.

Results

1. Alcohol plus clorazepate, 5mg/kg of body weight for 5 days.

clorazepate elevated the blood alcohol level significantly at both 15(p<0.01) and 45 minutes(p<0.05) after alcohol administration.

2. Alcohol plus clorazepate, 5mg/kg of body weight for 10 days.

In this group, clorazepate elevated also the blood alcohol level significantly at both 15(p<0.001) and 45 minutes(p<0.01) after alcohol administration.

3. Alcohol plus clorazepate, 10mg/kg of body weight for 7 days.

In this group, clorazepate caused also significant elevation of the blood alcohol level at both 15(p<0.001) and 45 minutes(p<0.5) after alcohol administration.

4. Alcohol plus medazepam, 5mg/kg of body weight for 7 days.

Medazepam did not change the blood alcohol level significantly at both 15(p>0.1) and 45 minutes(p>0.5) after alcohol administration.

5. Alcohol plus medazepam, 5mg/kg of body weight for 10 days.

In this group, medazepam elevated the blood alcohol level significantly at both 15(p<0.05) and 45 minutes(p<0.05) after alcohol administration.

6. Alcohol plus medazepam, 10mg/kg of body weight for 7 days.

In this group, medazepam elevated also the blood alcohol level significantly at both 15(p<0.001) and 45 minutes(p<0.05) after alcohol administration.

Conclusion

1. Clorazepate, when administered orally in either dosage of 5 mg/kg of body weight daily for 5 days or 7 days, or 10mg/kg of body weight daily for 7 days elevated the blood alcohol level significantly at both 15 and 45 minutes after alcohol administration.

2. Medazepam, when administered orally in either dosage of 5mg/kg of body weigth for 10 days, or 10mg/kg of body weight for 7 days elevated the blood alcohol level significantly at both 15 and 45 minutes after alcohol administration, while there's no significant elevation in a dosage of 5mg/kg of body weight for 7 days at both 15 and 45 minutes after alcohol administration.