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Pharmacokinetic study of aniracetam in elderly patients with cerebrovascular disease
ELSEVIER
Behavioural Brain Research 83 (1997) 243-244
BEHAVIOURAL BRAIN RESEARCH
Research report
Pharmacokinetic study of aniracetam in elderly patients with cerebrovascular disease H. Endo a.., T. Tajima a, H. Yamada a, A. Igata ~, Y. Yamamoto b, H. Tsuchida b, y. Nakashima b, Y. Suzuki c, H. Ikari c, A. Iguchi c a Department of Geriatrics, National Chubu Hospital, Ohbu 474, Japan b Research Laboratories, Toyama Chemical Co. Ltd. Shinjyuku, Tokyo 160, Japan c Department of Geriatrics, Nagoya University, Nagoya 466, Japan
Received 8 July 1994; revised 14 May 1995; accepted 14 May 1995
Abstract The clinical pharmacokinetics of the cognitive enhancer, aniracetam (200 mg), was studied in elderly patients with cerebrovascular disease (CVD) and compared with those of young healthy volunteers. Six female hospitalized patients (mean age 84.5 yearsl were used in this study. The serum level of anisic acid and p-methoxyhippuric acid, major metabolites of aniracetam, reached a peak at 2 h after oral administration, and returned to basal level by 6 h. Mean creatinine clearance was 20--30 ml/min. The t1,,2 of metabolites was increased by 4- to 7-fold in the elderly patients compared with young volunteers. This study showed that t . . . . tl/2, and AUC were enlarged in the elderly; however, no clinical side effects were observed. Keywords: Aniracetam; Elderly; Pharmacokinetics; Cerebrovasculardisease; Nootropic
1. Introduction
2. Materials and methods
Aniracetam is a novel nootropic drug which shows a protective action against memory and learning loss in animal models 1-1,3,5]. Beneficial effects of this compound on cognitive function are expected in patients with senile dementia [6], since it activates cholinergic neurons and thus promotes neuronal transmission. There are several metabolites of aniracetam which are considered to act as modulators in the central nervous system (CNS), and also have preventive effects for symptoms, such as anxiety, irritation and depressive mood, in patients with CVD. On the other hand, there are some difficulties in the drug treatment for elderly people, because they can have renal dysfunction progressing with age or other chronic alterations of metabolic processes. There are few clinical pharmacokinetic data related to cerebrovascular dilators or activators. In order to understand the clinically effective dose of aniracetam with minimum side effects in treating patients with CVD, we studied the pharmacokinetics of aniracetam in elderly patients and compared it with that of young subjects.
Subjects were 6 female hospitalized patients with CVD (mean age 84.5 years). The serum creatinine level of 5 patients was within normal limits. One patient, whose creatinine level was 2.7 mg/ml had renal failure due to diabetes mellitus. To study the pharmacokinetics of aniracetam, blood was drawn at 0.025, 0.5, 1, 2, 4 and 24 h after administration and the concentration of the metabolites was measured. Then Cmax (the highest concentration of the compound), tl/2 (the time of 50% excretion of the drug) and AUC (the area under the concentration-time curve) were calculated from the data gained. Study of young volunteers with aniracetam was carried out by Honma et al. [2]. Data were analyzed by a two-compartment model. Informed consent was taken from all patients.
* Corresponding author.
3. Results Fig. 1 shows the time course concentration of anisic acid and p-metoxyhippuric acid after oral administration of aniracetam (200 rag). The serum level of both metabo-
0166-4328/97/$17.00Copyright © 1997 ElsevierScienceB.V. All rights reserved PH S0166-4328 (96)00127- 1
244
H. Endo et al./Behavioural Brain Research 83 (1997) 243-244
Table 1 Comparison of pharmacokinetic parameters after a single dose of aniracetam to young and old subjects Metabolite
Old
Anisic acid p-Metoxyhippuric acid 2-Pyrrolidinone Succinimide
Younga
Cmax
/max
[~J2
AUC
Cm~~
t~x
t1,,2
AUC
7.96 2.90 0.332 0.793
1.67 1.41 2.17 5.00
3.48 9.5 11.5 47.2
51.5 21.2 2.5 13.7
7.73 2.06 0.326 0.578
0.71 0.75 0.88 5.83
0.79 NA 1.58 NA
9.25 2.25 0.71 NA
"The young group data are from the study by Honma et al. [2], which represent the parameters of each metabolite when aniracetam (300 mg) was administered to 6 healthy young volunteers (mean age 31.0 years).
lites of aniracetam reached a peak at 2 h after oral administration, and returned to basal level by 6 h. Table 1 shows pharmacokinetic parameters. As seen in Table 1, tl/2 of the metabolites was increased by 4- to 7-fold in elderly patients compared with young volunteers. It also shows that tmax and AUC were enlarged in the elderly. Mean creatinine clearance was 20-30 ml/min. The concentration of the metabolites in a patient with diabetic nephropathy was elevated to an abnormal level (more than 10-fold higher than the average level of old group). No side effects were found in symptoms and laboratory data on this study.
4. Discussion
Aniracetam acts as a positive modulator of AMPAsensitive glutamate receptors in a variety of nervous systems. There are 5 major metabolites in aniracetam [4]. They are anisic acid, p-methoxyhippuric acid, 2-pyrrolidinone, conjugates of glycine and glucuronide, and succinimide. It not yet known what kind of metabolites affects the CNS. There is a report which observed that 2-pyrrolidinone lengthened mouse survival time following hemicholinium injection into the brain [4]. Therefore, we can hypothesize that 2-pyrrolidinone is a gg/ml 0.8
IIII~,IL ' ~lLid
0.4
[
pn ~
1
2
pputu~a,., i d x ~
4
6
(h)
Fig. 1. Coneentration of metabolites of aniracetam after a single administration (200 mg).
candidate which is effective in the CNS. Aniracetam undergoes complete metabolism very rapidly in vivo, and after oral administration, concentrations of the intact compound in biological fluids are extremely low [4]. Patients administered aniracetam showed a statistically significant improvement versus baseline in the psychobehavioral parameters, while in the placebo group, a steady deterioration was observed [6], which implies the utility of the drug for the treatment of cognitive dysfunction in the elderly. Finally, it is necessary to study the drug monitoring in cerebro activators as well as anticonvulsants or antiseptic drugs to prevent side effects in elderly patients, because these cognitive enhancers were given to the elderly, who have low creatinine clearance as was confirmed in this study. The results showed that a lower dose of medication is recommended in the treatment of elderly patients, and that it is necessary to monitor the serum concentration of the drug in order to decide the proper therapeutic dose required.
References [1] Bartolini, L., Risaliti, R. and Pepeu, G., Effects of scopolamine and nootropic drugs on rewarded alternation in a T-maze, Pharmacol. Biochem. Behav., 43(4) (1992) 1161-1164. [2] Honma, A., Ikeda, K., Udo, N., Sadamori, M., Hasegawa, K. et al. Clinical phase I study on aniracetam, J. Clin. Ther. Med., 2 (1986) 929-952. [3] Martin, J.R., Cumin, R., Aschwanden, W., Moreau, J.L., Jenck, F. and Haefely, W.E., Aniracetam improves radial maze performance in rats, Neuroreport, 3(1)(1992) 81-83. [4] Mayersohn, M., Roncari, G. and Wendt, G., Disposition pharmacokinetics and metabolism of aniracetam in animals, Drug Invest., Suppl. 1, 3 (1993) 73-95. [5] Nagasaka, T., Momose, K., Hamaguchi, F., Yamada, K., Yamada, H. and Suzuki, Y., Synthesis of 1-trans-cinnamoyl- and 1-trans3-(pyridyl)acryloyl}-2- pyrrolidinones derivatives and their effect on hemicholinium-induced impairment of water maze learning in mice, Yakugaku Zasshi, 112(2)[1992) 100-107. [6] Senin, U., Abate, G., Fieschi, C., Gori, G., Guala, A., Marini, G., Villardita, C. and Parnetti, L., Aniracetam in the treatment of senile dementia of Alzheimer type (SDAT); results of a placebo controlled multicentre clinical study, Eur. Neuropsychopharmacol., 1(4) (1991) 511-517.
Behavioural Brain Research 83 (1997) 243-244
BEHAVIOURAL BRAIN RESEARCH
Research report
Pharmacokinetic study of aniracetam in elderly patients with cerebrovascular disease H. Endo a.., T. Tajima a, H. Yamada a, A. Igata ~, Y. Yamamoto b, H. Tsuchida b, y. Nakashima b, Y. Suzuki c, H. Ikari c, A. Iguchi c a Department of Geriatrics, National Chubu Hospital, Ohbu 474, Japan b Research Laboratories, Toyama Chemical Co. Ltd. Shinjyuku, Tokyo 160, Japan c Department of Geriatrics, Nagoya University, Nagoya 466, Japan
Received 8 July 1994; revised 14 May 1995; accepted 14 May 1995
Abstract The clinical pharmacokinetics of the cognitive enhancer, aniracetam (200 mg), was studied in elderly patients with cerebrovascular disease (CVD) and compared with those of young healthy volunteers. Six female hospitalized patients (mean age 84.5 yearsl were used in this study. The serum level of anisic acid and p-methoxyhippuric acid, major metabolites of aniracetam, reached a peak at 2 h after oral administration, and returned to basal level by 6 h. Mean creatinine clearance was 20--30 ml/min. The t1,,2 of metabolites was increased by 4- to 7-fold in the elderly patients compared with young volunteers. This study showed that t . . . . tl/2, and AUC were enlarged in the elderly; however, no clinical side effects were observed. Keywords: Aniracetam; Elderly; Pharmacokinetics; Cerebrovasculardisease; Nootropic
1. Introduction
2. Materials and methods
Aniracetam is a novel nootropic drug which shows a protective action against memory and learning loss in animal models 1-1,3,5]. Beneficial effects of this compound on cognitive function are expected in patients with senile dementia [6], since it activates cholinergic neurons and thus promotes neuronal transmission. There are several metabolites of aniracetam which are considered to act as modulators in the central nervous system (CNS), and also have preventive effects for symptoms, such as anxiety, irritation and depressive mood, in patients with CVD. On the other hand, there are some difficulties in the drug treatment for elderly people, because they can have renal dysfunction progressing with age or other chronic alterations of metabolic processes. There are few clinical pharmacokinetic data related to cerebrovascular dilators or activators. In order to understand the clinically effective dose of aniracetam with minimum side effects in treating patients with CVD, we studied the pharmacokinetics of aniracetam in elderly patients and compared it with that of young subjects.
Subjects were 6 female hospitalized patients with CVD (mean age 84.5 years). The serum creatinine level of 5 patients was within normal limits. One patient, whose creatinine level was 2.7 mg/ml had renal failure due to diabetes mellitus. To study the pharmacokinetics of aniracetam, blood was drawn at 0.025, 0.5, 1, 2, 4 and 24 h after administration and the concentration of the metabolites was measured. Then Cmax (the highest concentration of the compound), tl/2 (the time of 50% excretion of the drug) and AUC (the area under the concentration-time curve) were calculated from the data gained. Study of young volunteers with aniracetam was carried out by Honma et al. [2]. Data were analyzed by a two-compartment model. Informed consent was taken from all patients.
* Corresponding author.
3. Results Fig. 1 shows the time course concentration of anisic acid and p-metoxyhippuric acid after oral administration of aniracetam (200 rag). The serum level of both metabo-
0166-4328/97/$17.00Copyright © 1997 ElsevierScienceB.V. All rights reserved PH S0166-4328 (96)00127- 1
244
H. Endo et al./Behavioural Brain Research 83 (1997) 243-244
Table 1 Comparison of pharmacokinetic parameters after a single dose of aniracetam to young and old subjects Metabolite
Old
Anisic acid p-Metoxyhippuric acid 2-Pyrrolidinone Succinimide
Younga
Cmax
/max
[~J2
AUC
Cm~~
t~x
t1,,2
AUC
7.96 2.90 0.332 0.793
1.67 1.41 2.17 5.00
3.48 9.5 11.5 47.2
51.5 21.2 2.5 13.7
7.73 2.06 0.326 0.578
0.71 0.75 0.88 5.83
0.79 NA 1.58 NA
9.25 2.25 0.71 NA
"The young group data are from the study by Honma et al. [2], which represent the parameters of each metabolite when aniracetam (300 mg) was administered to 6 healthy young volunteers (mean age 31.0 years).
lites of aniracetam reached a peak at 2 h after oral administration, and returned to basal level by 6 h. Table 1 shows pharmacokinetic parameters. As seen in Table 1, tl/2 of the metabolites was increased by 4- to 7-fold in elderly patients compared with young volunteers. It also shows that tmax and AUC were enlarged in the elderly. Mean creatinine clearance was 20-30 ml/min. The concentration of the metabolites in a patient with diabetic nephropathy was elevated to an abnormal level (more than 10-fold higher than the average level of old group). No side effects were found in symptoms and laboratory data on this study.
4. Discussion
Aniracetam acts as a positive modulator of AMPAsensitive glutamate receptors in a variety of nervous systems. There are 5 major metabolites in aniracetam [4]. They are anisic acid, p-methoxyhippuric acid, 2-pyrrolidinone, conjugates of glycine and glucuronide, and succinimide. It not yet known what kind of metabolites affects the CNS. There is a report which observed that 2-pyrrolidinone lengthened mouse survival time following hemicholinium injection into the brain [4]. Therefore, we can hypothesize that 2-pyrrolidinone is a gg/ml 0.8
IIII~,IL ' ~lLid
0.4
[
pn ~
1
2
pputu~a,., i d x ~
4
6
(h)
Fig. 1. Coneentration of metabolites of aniracetam after a single administration (200 mg).
candidate which is effective in the CNS. Aniracetam undergoes complete metabolism very rapidly in vivo, and after oral administration, concentrations of the intact compound in biological fluids are extremely low [4]. Patients administered aniracetam showed a statistically significant improvement versus baseline in the psychobehavioral parameters, while in the placebo group, a steady deterioration was observed [6], which implies the utility of the drug for the treatment of cognitive dysfunction in the elderly. Finally, it is necessary to study the drug monitoring in cerebro activators as well as anticonvulsants or antiseptic drugs to prevent side effects in elderly patients, because these cognitive enhancers were given to the elderly, who have low creatinine clearance as was confirmed in this study. The results showed that a lower dose of medication is recommended in the treatment of elderly patients, and that it is necessary to monitor the serum concentration of the drug in order to decide the proper therapeutic dose required.
References [1] Bartolini, L., Risaliti, R. and Pepeu, G., Effects of scopolamine and nootropic drugs on rewarded alternation in a T-maze, Pharmacol. Biochem. Behav., 43(4) (1992) 1161-1164. [2] Honma, A., Ikeda, K., Udo, N., Sadamori, M., Hasegawa, K. et al. Clinical phase I study on aniracetam, J. Clin. Ther. Med., 2 (1986) 929-952. [3] Martin, J.R., Cumin, R., Aschwanden, W., Moreau, J.L., Jenck, F. and Haefely, W.E., Aniracetam improves radial maze performance in rats, Neuroreport, 3(1)(1992) 81-83. [4] Mayersohn, M., Roncari, G. and Wendt, G., Disposition pharmacokinetics and metabolism of aniracetam in animals, Drug Invest., Suppl. 1, 3 (1993) 73-95. [5] Nagasaka, T., Momose, K., Hamaguchi, F., Yamada, K., Yamada, H. and Suzuki, Y., Synthesis of 1-trans-cinnamoyl- and 1-trans3-(pyridyl)acryloyl}-2- pyrrolidinones derivatives and their effect on hemicholinium-induced impairment of water maze learning in mice, Yakugaku Zasshi, 112(2)[1992) 100-107. [6] Senin, U., Abate, G., Fieschi, C., Gori, G., Guala, A., Marini, G., Villardita, C. and Parnetti, L., Aniracetam in the treatment of senile dementia of Alzheimer type (SDAT); results of a placebo controlled multicentre clinical study, Eur. Neuropsychopharmacol., 1(4) (1991) 511-517.