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Effect of valproic acid and verapamil on metabolic changes in rat tissues during alcohol withdrawal
329
Alcoholism and Substance Dependence Tuesday, 20 October 1992
Piatelet paroxetine binding in alcoholics
Mellerup, E.T., Bech, P., Lauritzen, L., Lunde, M. and Plenge, P. Institute of Neuropsychiatry, Rigshospitalet-6102, DK-2100 Copenhagen Key words: Paroxetine binding; Platelets; Alcoholics Platelet paroxetine binding was analysed in 24 abstinent alcoholics and 18 control persons. The alcoholics had significantly more binding sites than the control persons. The mean Hamilton depression score for the alcoholics was 11, and when the Newcastle rating scale was used in order to subdivide the alcoholics after type of depression, it was found that they were all on the non-endogeneons type. Alcoholics with a low Newcastle score had higher platelet paroxetine binding than alcoholics with a higher Newcastle score, who had the same amount of binding as the control persons. The increased platelet paroxetine binding may indicate an increased serotonin uptake and thus a decreased serotonergic function in alcoholics. Determination of platelet paroxetine binding may thus be a way to identify alcoholics, who may benefit from treatment with serotonin uptake inhibitors.
Effect of valproic acid and verapamil on metabolic changes in rat tissues during alcohol withdrawal
Pronko, P.S., Kuzmich, A.B., Abakumov, G.Z. and Velichko, M.G. Institute of Biochemistry, Byelorgssian Academy of Sciences, Grodno 230009, Byelorussia Key words: Withdrawal; Ethanol; Lipid peroxidation; Valproic acid; Verapamil There are experimental and clinical data that alcohol withdrawal signs are decreased by calcium channel blockers and valproic acid. However, little information is available about effects of these drugs on metabolic changes related to ethanol and acetaldehyde oxidation in the organism. In this connection it is of interest to study effects of the calcium channel blocker, verapamil, and valproic acid on blood and liver concentrations of ethanol, acetaldehyde, lactate and pyruvate as well as lipid peroxidation during the ethanol withdrawal syndrome in rats. To produce physical dependence, rats were administered ethanol orally (from 5 to 3-6 g/kg 2 times a day over 5 days). From the fourth day some of them were supplementary injected with either valproic acid (200 mg/kg i.p.) or verapamil (20 mg/kg i.p.). Control animals received intragastrically water. Each of the 4 groups included 10 animals. Rats were killed on
330 the sixth day of experiment 19 h after the last dose of ethanol and 1 h after the last injection of the drugs. During the experiment one rat died in the ethanol-treated group, 1- in the group receiving ethanol and valproic acid. Valproic acid prevented lactate accumulation in the blood and liver during ethanol withdrawal, increased the lipid peroxide levels and decreased the antioxidative activity in blood plasma. Verapamil administration decreased the pyruvate concentration in the liver compared to the control and ethanol groups and enhanced the lipid peroxide levels in blood plasma, but it decreased the same parameter in the liver of the animals. In the additional experiment, it was shown that the single valproate injection (20 mg/kg, i.p.) 1 h before ethanol (1 g/kg) significantly decreased the ethanol elimination rate constant, enhanced the half-time of ethanol elimination and lowered the acetaldehyde concentration in blood. Thus, the decreasing effect of valproic acid on the ethanol elimination rate can explain the higher mortality in the group receiving ethanol and this drug and the absence of increased lactate levels like it was found in the ethanol group. One could suggest that calcium channel blockers and valproate treatment during ethanol intoxication and at the withdrawal period can produce not only specific neurochemical effects but nonspeeific metabolic changes and interfere with ethanol metabolism.
Optimized carbamazepine dosing in alcohol withdrawal Griiner, J.F., Micke, G. and Domek, D. Psychiatrische Klinik, Stadtkrankenhaus Offenbach, Starkenburgring 66, 6050 Offenbach, Germany Key words: Carbamazepine; Alcohol withdrawal; Dosage; Blood levels
Most abstinence fits occur in early alcohol withdrawal, so that therapeutic carbamazepine (CBZ) levels of 4-12 pg/ml should be established as soon as possible after hospitalization. From published data and a pilot study it was concluded that the approximate loading dose (D L) and maintenance dose (in mg Tegretol retard s) can be calculated by multiplying the body weight (in kg) by 12 and 4 respectively. This was tested using the following dosage schedule: Day
Weight (kg) < 62.5
1
DL
62.5 - 87.5
> 87.5
300 + 600
400 + 800
(1/3 Tegretol suspension a + 2/3 Tegretol retardS): 200 + 400
Regular dosing (Tegretol retard s where possible): 9 a.m.
9 p.m.
9 a.m.
9 p.m.
9 a.m.
9 p.m.
200 0 0 0 300 100
300 300 200 0 300 100
200 0 0 0 400 200
400 400 200 0 400 200
Follow-up doses on day 1 according to time of D L" 0 a.m. 6 a.m. 12 a.m. 6 p.m. 2/4 5-7
-
6 a.m. 12 a.m. 6 p.m. 12 p.m.
100 0 0 0 200 100
200 200 100 0 200 100
Means -+ SDs and ranges of the CBZ levels of 12 alcoholics I hour after D L and at 9 a.m. on day 2, 5, and 8 were 3.94 -+ 1.28 (1.60-6.27), 8.65 -+ 1.41 (6.05-10.35), 7.42 +- 2.60 (3.81-12.75), and 3.82 +- 1.09 (2.62-6.10) lag/ml respectively. Thus in
Alcoholism and Substance Dependence Tuesday, 20 October 1992
Piatelet paroxetine binding in alcoholics
Mellerup, E.T., Bech, P., Lauritzen, L., Lunde, M. and Plenge, P. Institute of Neuropsychiatry, Rigshospitalet-6102, DK-2100 Copenhagen Key words: Paroxetine binding; Platelets; Alcoholics Platelet paroxetine binding was analysed in 24 abstinent alcoholics and 18 control persons. The alcoholics had significantly more binding sites than the control persons. The mean Hamilton depression score for the alcoholics was 11, and when the Newcastle rating scale was used in order to subdivide the alcoholics after type of depression, it was found that they were all on the non-endogeneons type. Alcoholics with a low Newcastle score had higher platelet paroxetine binding than alcoholics with a higher Newcastle score, who had the same amount of binding as the control persons. The increased platelet paroxetine binding may indicate an increased serotonin uptake and thus a decreased serotonergic function in alcoholics. Determination of platelet paroxetine binding may thus be a way to identify alcoholics, who may benefit from treatment with serotonin uptake inhibitors.
Effect of valproic acid and verapamil on metabolic changes in rat tissues during alcohol withdrawal
Pronko, P.S., Kuzmich, A.B., Abakumov, G.Z. and Velichko, M.G. Institute of Biochemistry, Byelorgssian Academy of Sciences, Grodno 230009, Byelorussia Key words: Withdrawal; Ethanol; Lipid peroxidation; Valproic acid; Verapamil There are experimental and clinical data that alcohol withdrawal signs are decreased by calcium channel blockers and valproic acid. However, little information is available about effects of these drugs on metabolic changes related to ethanol and acetaldehyde oxidation in the organism. In this connection it is of interest to study effects of the calcium channel blocker, verapamil, and valproic acid on blood and liver concentrations of ethanol, acetaldehyde, lactate and pyruvate as well as lipid peroxidation during the ethanol withdrawal syndrome in rats. To produce physical dependence, rats were administered ethanol orally (from 5 to 3-6 g/kg 2 times a day over 5 days). From the fourth day some of them were supplementary injected with either valproic acid (200 mg/kg i.p.) or verapamil (20 mg/kg i.p.). Control animals received intragastrically water. Each of the 4 groups included 10 animals. Rats were killed on
330 the sixth day of experiment 19 h after the last dose of ethanol and 1 h after the last injection of the drugs. During the experiment one rat died in the ethanol-treated group, 1- in the group receiving ethanol and valproic acid. Valproic acid prevented lactate accumulation in the blood and liver during ethanol withdrawal, increased the lipid peroxide levels and decreased the antioxidative activity in blood plasma. Verapamil administration decreased the pyruvate concentration in the liver compared to the control and ethanol groups and enhanced the lipid peroxide levels in blood plasma, but it decreased the same parameter in the liver of the animals. In the additional experiment, it was shown that the single valproate injection (20 mg/kg, i.p.) 1 h before ethanol (1 g/kg) significantly decreased the ethanol elimination rate constant, enhanced the half-time of ethanol elimination and lowered the acetaldehyde concentration in blood. Thus, the decreasing effect of valproic acid on the ethanol elimination rate can explain the higher mortality in the group receiving ethanol and this drug and the absence of increased lactate levels like it was found in the ethanol group. One could suggest that calcium channel blockers and valproate treatment during ethanol intoxication and at the withdrawal period can produce not only specific neurochemical effects but nonspeeific metabolic changes and interfere with ethanol metabolism.
Optimized carbamazepine dosing in alcohol withdrawal Griiner, J.F., Micke, G. and Domek, D. Psychiatrische Klinik, Stadtkrankenhaus Offenbach, Starkenburgring 66, 6050 Offenbach, Germany Key words: Carbamazepine; Alcohol withdrawal; Dosage; Blood levels
Most abstinence fits occur in early alcohol withdrawal, so that therapeutic carbamazepine (CBZ) levels of 4-12 pg/ml should be established as soon as possible after hospitalization. From published data and a pilot study it was concluded that the approximate loading dose (D L) and maintenance dose (in mg Tegretol retard s) can be calculated by multiplying the body weight (in kg) by 12 and 4 respectively. This was tested using the following dosage schedule: Day
Weight (kg) < 62.5
1
DL
62.5 - 87.5
> 87.5
300 + 600
400 + 800
(1/3 Tegretol suspension a + 2/3 Tegretol retardS): 200 + 400
Regular dosing (Tegretol retard s where possible): 9 a.m.
9 p.m.
9 a.m.
9 p.m.
9 a.m.
9 p.m.
200 0 0 0 300 100
300 300 200 0 300 100
200 0 0 0 400 200
400 400 200 0 400 200
Follow-up doses on day 1 according to time of D L" 0 a.m. 6 a.m. 12 a.m. 6 p.m. 2/4 5-7
-
6 a.m. 12 a.m. 6 p.m. 12 p.m.
100 0 0 0 200 100
200 200 100 0 200 100
Means -+ SDs and ranges of the CBZ levels of 12 alcoholics I hour after D L and at 9 a.m. on day 2, 5, and 8 were 3.94 -+ 1.28 (1.60-6.27), 8.65 -+ 1.41 (6.05-10.35), 7.42 +- 2.60 (3.81-12.75), and 3.82 +- 1.09 (2.62-6.10) lag/ml respectively. Thus in