Medazepam 및 cloxazolam이 가토 혈중 주정농도에 미치는 영향에 관한 실험적 연구

Abstract

[한글]

Medazepam은 benzodiazepine제 약물로서 chilordiazepoxide와 다소 작용이 비슷한 점이 있는 항불안 약물로 임상에 널리 사용되고 있다. 이 약물은 현저한 taming effct, 근육이완 작용과 항경련작용을 갖고 있고, 부작용은 경미하고 독성이 낮은 것이 특징이다. 많은 연구결과, 사람과 개에서 medazepam을 경구투여후 흡수가 신속하고 대사가 빨라 혈장에서 거의 축적되지 않는 것으로 시사되었다.

한편 cloxazolam은 medazepam보다 더 최근에 개발된 benzodiazepinerP 약물이다.

일부 향정신성 약물들이 주정효과를 강화시킴으로써 이 약물들의 복용중 음주로 인해교통사고가 일어날 위험이 더 증대될 수 있기 때문에 수정과의 상호작용을 알아 보기 위해 모든 향정신성 약물들에 대해 시험해 볼 필요가 있다고 생각된다. 최근 chlorpromazino과 lithium을 포함하는 많은 향정신성 약물들이 가토 혈중 주정농도를 높인 것으로 보고되었다. 이런 사실에 비추어, medazepam 및 cloxazolam이 가토 혈중 주정농도에 미치는영향을 규명해 본다는 것은 이론적으로나 실제적으로 매우 의의있는 바로 고려되어 본 연구를 시행하였다.

실험재료 및 방법

1. 실험동물은 체중 2.7∼3.0 kg 성숙한 자웅 가토를 사용하였다.

2. 대조군에서는 주정만 단독 투여하였다.

3. 실험군은 주정 + medazepam (5mg/kg), 주전 + medazepam (10mg/kg), 주정 + cloxazolam (2mg/kg)으로 투여군을 넷으로 나누고, 투여기간은 각각 연5일 및 연 70일간으로 정하였다.

4. Medazepam은 가토 체중 매 kg당 5mg 및 10mg씩, cloxazolam은 매 kg당 1mg 및 2mg씩 매일 같은 시각에 1회 경구투여하였고, 최종일에는 주정정주 90분 전에 투여하였다.

5. 주정투여는 20 vol.% ethanol용액을 체중 매 kg당 5.0mg를 이변 정맥 내로 5분간에걸쳐 서서히 주사하였다.

6. 채혈은 모든 군에서 주정투여후 15분과 45분에 심장천자로 시행하였다.

7. 주정의 혈중농도는 Cavett씨 방법에 의해 측정하였다.

실 험 성 적

1. medazepam을 5mg/kg씩 연5일간 및 연10일간 투여시 다만 제10일쩨 45분에서 혈중 주정농도를 유의하게 높인 것 이외에 주정투여후 15분 및 45분의 혈중 주정농도에 각각 유의한 변화가 없었다.

2. Medazepam을 10mg/kg씩 연5일간 및 연10일간 투여시 주정투여후 15분 및 45분에서각각 혈중 주정농도를 유의하게 높였으나 연5일간 투여군의 45분에서는 유의한 변화가 없었다.

3. Cloxazolam을 1mg/kg씩 연5일 및 연10일간 투여시 주정투여후 15분 및 45분에서 각각 모두 혈중 주정농도에 유의한 변화가 없었다.

4. Cloxazolam을 2mg/kg씩 연5일 및 연10일간 투여시 주정투여후 15분 및 45분에서 각각 모두 혈중 주정농도를 유의하게 높였다.

이러한 결과들을 투여량이 같고 기간이 다른 군들을 서로 비교할 때 각각 모두 유의한 변화는 발견되지 않았다.

[영문]

Medazepam is a diazepam analouge with a 2-ketone omitted, and is used as an antianxiety agent. The drug shows the characteristic taming effect, muscle relaxant and anticonvulsant properties with minimal side effects and low toxicity. The pharmacodynamic aspects of the drug indicated rapid onset of absorption and rapid

biotransformation of oral medazepam in men and dogs, with little accumulation in the plasma. It is also found that diazepam is an important metabolite of medazepam in rats and men, showing a major potency in clilical actions. Cloxazolam is a newer member of the benzodiazepine derivatives, which possess considerable calming effects.

It is suggested that the potentiation of alcohol by some psychotropic drugs may, among other things, increase the risk of traffic accidents. Hence, it is necessary to test all psychotropic drugs for their interaction with alcohol. It has been recently reported that many psychotropic drugs including chlorpromazine and lithium, elevated the blood alcohol level in rabbits. In view of these finding, the author conducted an animal experiment to investigate the effect of medazepam and cloxazolam on blood level of alcohol in rabbits.

Material and Method

1. The experimental work was done on mature rabbits of both sexes, weighing about 2 to 3 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 4 subgroups;

a) alcohol plus medazepam, 5 mg/kg of body weight,

b) alcohol plus medazepam, 10 mg/kg of body weight,

c) alcohol plus cloxazolam, 1 mg/kg of body weight, and

d) alcohol plus cloxazolam, 2 mg/kg of body weight.

5. These above groups were father divided into 2 subgroups in which one subgroup was given these drugs respectively for 5 days and another for 10 days.

6. Each medaaepam or cloxazolam was orally given in a single dose at a fixed time. The last dose was given one hour and a half before alcohol administration.

7. In all groups 20 vol.% ethanol solution was slowly was given in a dose of 5.0 ml/kg of body weight for 5 minutes by intravenous routs.

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

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

Results

1. Alcohol plus medazepam, 5 mg/kg of body weight for 5 days. Medazepam caused no significant change in the blood alcohol level at both 15 and 45 minutes after alcohol administration (p>0.05)

2. Alcohol plus madazeapam, 5 mg/kg of body weight for 10 days. In this group, no significant change was shown in the blood alcohol level at 15 minutes (p>0.05) but significant elevation of blood alcohol level was noted at 45 minutes (p<0.01) after alcohol administration.

3. Alcohol plus medazepam, 10 mg/kg of body weight for 5day. In this group, medazepam elevated the blood alcohol level significantly at 15 minutes (p<0.05) but caused no significant change in the blood alcohol level at 45 minutes (p>0.05) after alcohol administration.

4. Alcohol plus medazepam, 10 mg/kg of body weight for 10 days, In this group, medazepam elevated the blood alcohol level significantly at both 15 (p<0.01) and 45 minutes (p<0.05) after alcohol administration.

5. Alcohol plus cloxazolam, 1 mg/kg of body weight for 5 days. Cloxazolam caused no significant change in the blood alcohol level at both 15 and 45 minutes after alcohol administration (p>0.05).

6. Alcohol plus cloxazolam, 1 mg/kg of body weight for 10 days. In this group, no significant change in the blood alcohol level was also shown at both 15 and 45 minutes after alcohol administration.

7. Alcohol plus cloxazolam, 2 mg/kg of body weight for 5 day. In this group, significant elevation of the blood alcohol level was noted at both 15 (p<0.005) and 45 minutes (p<0.001) after alcohol administration.

8. Alcohol plus cloxazolam, 2 mg/kg of body weight for 10 days. In this group, cloxazolam also caused significant elevation in the blood alcohol level at both 15 (p<0.025) and 45 minutes (p<0.001) after alcohol administration.

9. No statistical significance was obtained in the difference of the blood alcohol level of both these drugs at the same dose administered between for 5 days and 10 days (p>0.05).

Conclusions

1. Medazepam, when administerd orally in a dose of 5 mg/kg of body weight daily for 5 or 10 days, did not elevate the blood alcohol level significantly at both 15 and 45 minutes after alcohol administration except significant elevation in the

blood alcohol level at 45 minutes of the group administered for 10 days.

2. Medazepam, when administered orally in a dose of 10 mg/kg of body weight dailt elevated the blood alcohol level significantly at both 15 and 45 minutes except no significant elevation at 45 minutes of the group administered for 5 days.

3. Cloxazolam, when administered orally in a dose of 1 mg/kg of body weight daily for 5 or 10 days, did not elevate the blood alcohol significantly at both 15 and 45 minutes after alcohol administration.

4. Cloxazolam, when administered orally in a dose of 2 mg/kg of body weight dailt for 5 or 10 days, elevated blood alcohol level significantly at both 15 and 45 minutes after alcohol administration.

5. There was no significant difference in the blood alcohol level between the two subgroups in which each medazepam or cloxazolam was administered for 5 and 10 days respectively.