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Acamprosate effect on changes of transferrin levels in ethanol preferring and non-preferring rats
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44 outcome calculations (abstinence rate, cumulative abstinence duration) also showed a significant advantage over placebo. Apart from occasional diarrhoea, acamprosate was well tolerated. These results indicate that acamprosate is an effective pharmacological adjunct to psychosocial and behavioral treatment programs for the treatment of alcohol dependent patients without serious adverse events.
I P-3-51
Adrenal Gland Enlargement ReSUlting from Hyperactivity of the Pituitary-Adrenocortical System in Alcoholics Y. Ida, I. Shirao, S. Tsujimaru. Department of Neuropsychiatry, Kurume University School ofMedicine. Kurume, 830 Japan
Hyperactivity of hypothalamic-pituitary-adrenocortical (HPAj system in acute withdrawal period in alcoholics has been indicated by evidences of hypercortisoJism and a blunted response of ACTH after CRH challenge test. In the present study, we examined whether the adrenal gland enlargement may occur resulting from the hyperactivity of HPAsystem. We measured the adrenal gland volume of 23 male alcoholics on 2th and 2&th admission days and 13 normal male subjects at 16:00 by using CT-scan concomitantly with measuring levels of plasma ACTH levels and serum cortisol levels. Adrenal gland volume on 2th and 28th admission days was significantly larger than those of normal subjects. Serum cortisol levels on 2th admission day was significantly higher than those of normal subjects, although plasma ACTH levels on 2th admission day was significantly lower. On 2th admission day, adrenal gland volume showed a positive correlation with serum cortisol levels. Both levels of ACTH and cortisol returned to normal on 28th admission day. These data suggest that although the hyperactivity of the HPA system in acute withdrawal period could return to normal within four weeks after abstinence, the recovery of adrenal gland enlargement might be delayed more than that of function of the HPA system in alcoholics.
I p-3-sl
Treatment of Alcohol Withdrawal Delirium and Changes in Monoamine
N. Uchimura I , J. Nakamura 1• Y. Tsuchiyama I , Y. Nakazawa I, S. Yamada 2, H. Ohshirna 3, M. Ohshima 3. I Department of Neuropsychiatry. Kurume University School of Medicine, Japan: 2 Institute of Brain Diseases, Kurume University School ofMedicine, Kurume, Japan; 3 Ohshima Hospital, Saga, Japan The withdrawal symptoms which occur in chronic alcoholics within a few days after cessation of alcohol drinking include finger tremor, insomnia, autonomic symptoms and delirium tremens. It is very hard to predict the alcohol withdrawal syndrome, especially delirium tremens. In this study. high-dose mianserin (90-240 rug/day) was administered to 24 alcoholic patients with withdrawal symptoms since their admission. The clinical therapeutic effect of mianserin was investigated using Clinical Institute Withdrawal Assessment Scale. and the plasma concentration of mianserin, free-MHPG, HVA and 5-HIAA were measured pre-and post treatment. Four patients showed delirium tremens, while the other patients exhibited autonomic symptoms at admission. Only two of 20 patients developed delirium tremens after admission. The delirium tremens disappeared early without protraction within approximately three days after the consecutive administration of mianserin in 6 patients. The plasma mianserin concentration reached a therapeutic level within 24 hours after beginning the treatment. A significant positive correlation was noted between the mianserin concentration and the age, with elderly patients showing a higher concentration. The average plasma MHPG concentration in delirium group was higher than that in non delirium group. In both the groups. the plasma MHPG and HVA concentration gradually decreased after administration of mianserin, but, on the other hand the plasma 5-HIAA concentration increased after administration of mianserin. These results suggest that high dose mianserin therapy is effective against alcohol withdrawal delirium without protraction and prevent the development of delirium tremens, and the hyperactivity of norepinephirine metabolism is likely related to delirium tremens.
IP-3-7! Acamprosate Effect on Changes of Transferrin Levels in Ethanol Preferring andNon-Preferring Rats P. Mikolajczak, I. Okulicz-Kozaryn, E. Kamiriska, M. Sobieska I . Dept. of Pharmacology. University of Medical Sciences, Poznan. Poland: 1 Dept. of Clinical Immunology and Alergology, University of Medical Sciences, Poznan, Poland The evaluation of chronic ETOH drinking using the specific and sensitive markers of ETOH intake and abuse has been developed (Mihas A.A. et al., 1992. Borg S., et al., 1995, Sillanaukee P., 1995). Carbohydrate deficient transferrin (COT) has been reported to be one of the most accurate marker of chronic ethanol consumption (Tsutsumi M. et al., 1994, Kanitz R.D. et al.. 1994). Lately, we have reponed that the changes of transferrin (TF) levels have showed to be a possible marker demonstrating the difference between ethanol preferring [PREF) and non-preferring [NPREFj rats (Mikolajczak P., et al., 1995). Therefore, the investigation of possible changes of TF after acamprosate [ACAM) treatment, a novel anti-craving drug (Aubin H.1., et al., 1995. Paille F, et al., 1995), in chronically ethanol [ETOH) treated rats seemed to be interesting. Materials & Methods: Male Wistar rats housed individually in cages were pretreated with ETOH for 2 months ("=' 9 glkg/day). Animals preferring (» 50 total fluid intake [PREF» and non-preferring [NPREF) were used in this study (2 weeks preferring period). After preferring period both groups of rats were treated with ACAM (500 mglkg p.o.) for 10 consecutive days (lOx). Before the start of alcoholization, after 2 months of ETOH pretreatment, after ETOH preferring period and after 10xACAM treatment blood samples were collected and TF levels were determinared using the rocket immunoelectrophoretic method (Laurell C.S" 1973). Results: The different changes of TF levels in both investigated groups of animals were observed. In PREF group after IOxACAM treatment the significant lower 11.. levels were found in comparison to TF levels before ACAM premedication. On the contrary, in NPREF group multiple ACAM administration led to significant increase of TF levels when compared to its ACAM-untreated group. For the explanation these mentioned differences further investigations are needed. especially the assessment of TF microheterogeneity in both investigated groups could be helpful.
1 P-3-10 I
GlycinefNMDA Antagonists Reduce Amphetamine Disruptions in Prepulse Inhibition in the Rat LJ . Bristow, G.P. Cook, K L. SayweJl. Merck, Sharp and Dohme,
Neuroscience Research Centre, Harlow, U.K. Prepulse inhibition (PP!) is a measure of sensorimotor gating which is attenuated in schizophrenic patients and in rats treated with dopamine receptor agonists. In the present study we have de termined whether the gIycineINMDA receptor antagonist, 7-ch loro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinolone (L·70I,324) will reduce the disruption in PPI induced by amphetamine in the rat. Startle responses were recorded in male Wistar rats (320--450 g) using 6 SR-LAB (San Diego Instruments) stabilimeter chambers. In vehicle-pretreated animals. the startle response to a 40 msec, 120 dB tone (pulse) was significantly attenuated when preceded by a weak, &0 dB prepulse (mean startle response ± s.e. mean (n = 12 rats): pulse = 6 15 ± 67, prepulse + pulse = 265 ± 3&' , ' p < 0.05 compared to pulse-alone; % PPI (i.e. 100 x [pulse - (prepulse + pulse))fpulse) = 54 ± 6%). Pretreatment with amphetamine (4 rug/kg, s.c.) 20 min prior to testing significantly impaired PPI in the rat (mean startle response ± s.e. mean (n = 12 rats): pulse = 615 ± 8 1, prepulse + pulse = 538 ± 96' ; % PPI = 13 ± 9%' , , P < 0.05 compared to vehicle-treated rats) an effect which was significantly reduced in rats pretreated with L-701,324 (1 mg/kg, i.p.; % PPI = 39 ± 6%", 'p < 0.05 compared to vehicle/amphetamine treated rats). Thus, consistent with previous studies [lj suggesting that L-701,324 can attenuate activation of mesolimbic dopamine systems, the present study shows that I mg/kg L· 701,324 can reduce the disruption in PPI induced by amphetamine in the rat. (1] Bristow LJ, Flarrnan KL. Young L, Thorn L, Hutson PH, Tricklebank MD, Br. J. Pharmacol. 114 (1 995)321P.
44 outcome calculations (abstinence rate, cumulative abstinence duration) also showed a significant advantage over placebo. Apart from occasional diarrhoea, acamprosate was well tolerated. These results indicate that acamprosate is an effective pharmacological adjunct to psychosocial and behavioral treatment programs for the treatment of alcohol dependent patients without serious adverse events.
I P-3-51
Adrenal Gland Enlargement ReSUlting from Hyperactivity of the Pituitary-Adrenocortical System in Alcoholics Y. Ida, I. Shirao, S. Tsujimaru. Department of Neuropsychiatry, Kurume University School ofMedicine. Kurume, 830 Japan
Hyperactivity of hypothalamic-pituitary-adrenocortical (HPAj system in acute withdrawal period in alcoholics has been indicated by evidences of hypercortisoJism and a blunted response of ACTH after CRH challenge test. In the present study, we examined whether the adrenal gland enlargement may occur resulting from the hyperactivity of HPAsystem. We measured the adrenal gland volume of 23 male alcoholics on 2th and 2&th admission days and 13 normal male subjects at 16:00 by using CT-scan concomitantly with measuring levels of plasma ACTH levels and serum cortisol levels. Adrenal gland volume on 2th and 28th admission days was significantly larger than those of normal subjects. Serum cortisol levels on 2th admission day was significantly higher than those of normal subjects, although plasma ACTH levels on 2th admission day was significantly lower. On 2th admission day, adrenal gland volume showed a positive correlation with serum cortisol levels. Both levels of ACTH and cortisol returned to normal on 28th admission day. These data suggest that although the hyperactivity of the HPA system in acute withdrawal period could return to normal within four weeks after abstinence, the recovery of adrenal gland enlargement might be delayed more than that of function of the HPA system in alcoholics.
I p-3-sl
Treatment of Alcohol Withdrawal Delirium and Changes in Monoamine
N. Uchimura I , J. Nakamura 1• Y. Tsuchiyama I , Y. Nakazawa I, S. Yamada 2, H. Ohshirna 3, M. Ohshima 3. I Department of Neuropsychiatry. Kurume University School of Medicine, Japan: 2 Institute of Brain Diseases, Kurume University School ofMedicine, Kurume, Japan; 3 Ohshima Hospital, Saga, Japan The withdrawal symptoms which occur in chronic alcoholics within a few days after cessation of alcohol drinking include finger tremor, insomnia, autonomic symptoms and delirium tremens. It is very hard to predict the alcohol withdrawal syndrome, especially delirium tremens. In this study. high-dose mianserin (90-240 rug/day) was administered to 24 alcoholic patients with withdrawal symptoms since their admission. The clinical therapeutic effect of mianserin was investigated using Clinical Institute Withdrawal Assessment Scale. and the plasma concentration of mianserin, free-MHPG, HVA and 5-HIAA were measured pre-and post treatment. Four patients showed delirium tremens, while the other patients exhibited autonomic symptoms at admission. Only two of 20 patients developed delirium tremens after admission. The delirium tremens disappeared early without protraction within approximately three days after the consecutive administration of mianserin in 6 patients. The plasma mianserin concentration reached a therapeutic level within 24 hours after beginning the treatment. A significant positive correlation was noted between the mianserin concentration and the age, with elderly patients showing a higher concentration. The average plasma MHPG concentration in delirium group was higher than that in non delirium group. In both the groups. the plasma MHPG and HVA concentration gradually decreased after administration of mianserin, but, on the other hand the plasma 5-HIAA concentration increased after administration of mianserin. These results suggest that high dose mianserin therapy is effective against alcohol withdrawal delirium without protraction and prevent the development of delirium tremens, and the hyperactivity of norepinephirine metabolism is likely related to delirium tremens.
IP-3-7! Acamprosate Effect on Changes of Transferrin Levels in Ethanol Preferring andNon-Preferring Rats P. Mikolajczak, I. Okulicz-Kozaryn, E. Kamiriska, M. Sobieska I . Dept. of Pharmacology. University of Medical Sciences, Poznan. Poland: 1 Dept. of Clinical Immunology and Alergology, University of Medical Sciences, Poznan, Poland The evaluation of chronic ETOH drinking using the specific and sensitive markers of ETOH intake and abuse has been developed (Mihas A.A. et al., 1992. Borg S., et al., 1995, Sillanaukee P., 1995). Carbohydrate deficient transferrin (COT) has been reported to be one of the most accurate marker of chronic ethanol consumption (Tsutsumi M. et al., 1994, Kanitz R.D. et al.. 1994). Lately, we have reponed that the changes of transferrin (TF) levels have showed to be a possible marker demonstrating the difference between ethanol preferring [PREF) and non-preferring [NPREFj rats (Mikolajczak P., et al., 1995). Therefore, the investigation of possible changes of TF after acamprosate [ACAM) treatment, a novel anti-craving drug (Aubin H.1., et al., 1995. Paille F, et al., 1995), in chronically ethanol [ETOH) treated rats seemed to be interesting. Materials & Methods: Male Wistar rats housed individually in cages were pretreated with ETOH for 2 months ("=' 9 glkg/day). Animals preferring (» 50 total fluid intake [PREF» and non-preferring [NPREF) were used in this study (2 weeks preferring period). After preferring period both groups of rats were treated with ACAM (500 mglkg p.o.) for 10 consecutive days (lOx). Before the start of alcoholization, after 2 months of ETOH pretreatment, after ETOH preferring period and after 10xACAM treatment blood samples were collected and TF levels were determinared using the rocket immunoelectrophoretic method (Laurell C.S" 1973). Results: The different changes of TF levels in both investigated groups of animals were observed. In PREF group after IOxACAM treatment the significant lower 11.. levels were found in comparison to TF levels before ACAM premedication. On the contrary, in NPREF group multiple ACAM administration led to significant increase of TF levels when compared to its ACAM-untreated group. For the explanation these mentioned differences further investigations are needed. especially the assessment of TF microheterogeneity in both investigated groups could be helpful.
1 P-3-10 I
GlycinefNMDA Antagonists Reduce Amphetamine Disruptions in Prepulse Inhibition in the Rat LJ . Bristow, G.P. Cook, K L. SayweJl. Merck, Sharp and Dohme,
Neuroscience Research Centre, Harlow, U.K. Prepulse inhibition (PP!) is a measure of sensorimotor gating which is attenuated in schizophrenic patients and in rats treated with dopamine receptor agonists. In the present study we have de termined whether the gIycineINMDA receptor antagonist, 7-ch loro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinolone (L·70I,324) will reduce the disruption in PPI induced by amphetamine in the rat. Startle responses were recorded in male Wistar rats (320--450 g) using 6 SR-LAB (San Diego Instruments) stabilimeter chambers. In vehicle-pretreated animals. the startle response to a 40 msec, 120 dB tone (pulse) was significantly attenuated when preceded by a weak, &0 dB prepulse (mean startle response ± s.e. mean (n = 12 rats): pulse = 6 15 ± 67, prepulse + pulse = 265 ± 3&' , ' p < 0.05 compared to pulse-alone; % PPI (i.e. 100 x [pulse - (prepulse + pulse))fpulse) = 54 ± 6%). Pretreatment with amphetamine (4 rug/kg, s.c.) 20 min prior to testing significantly impaired PPI in the rat (mean startle response ± s.e. mean (n = 12 rats): pulse = 615 ± 8 1, prepulse + pulse = 538 ± 96' ; % PPI = 13 ± 9%' , , P < 0.05 compared to vehicle-treated rats) an effect which was significantly reduced in rats pretreated with L-701,324 (1 mg/kg, i.p.; % PPI = 39 ± 6%", 'p < 0.05 compared to vehicle/amphetamine treated rats). Thus, consistent with previous studies [lj suggesting that L-701,324 can attenuate activation of mesolimbic dopamine systems, the present study shows that I mg/kg L· 701,324 can reduce the disruption in PPI induced by amphetamine in the rat. (1] Bristow LJ, Flarrnan KL. Young L, Thorn L, Hutson PH, Tricklebank MD, Br. J. Pharmacol. 114 (1 995)321P.