149
EpilepsyRes., 8(1991) 149-152 Elsevier EPIRES 00377
Effects of acute valproic acid administration on carnitine plasma concentrations in epileptic patients
Roberto Riva”, Gaetano Zaccarab, Fiorenzo Albania, Giovanni Gallia, Roberto Campostrinib, Marco Paganinib and Agostino Baruzzia Institutes of Neurology,
Universities of “Bologna and bFlorence, Italy
(Received 20 July 1990; accepted 12 September 1990) Key words: Camitine; Valproic acid; Ammonia; Drug toxicity; Anticonvulsant; Epilepsy
Serial plasma samples collected after an acute administration of valproic acid (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P < 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total camitine was unchanged but free carnitine was decreased (P < 0.05) and camitine esters were increased (P < 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA toxicity or between patients with or without phenobarbital and phenytoin therapy. The data show that acute VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.
INTRODUCTION A decrease in carnitine plasma concentrations during chronic valproic acid (VPA) therapy has been reported2~‘2317~20. This effect has been considered important in determining both hyperammonemia and VPA encephalopathys~8*‘3,1s-22. Acute administration of VPA has been found to alter ammonia metabolism, and the degree of this
acute alteration has been shown to predict the appearance of side-effects during the first month of chronic VPA therap$5T26. This study aimed to establish if acute VPA administration gives rise to acute changes in carnitine plasma concentrations, and whether these changes are correlated with acute changes in venous ammonia levels (able to identify subjects at ‘risk’) and clinical status. METHODS
Correspondence to: Riva Roberto, Institute of Neurology, University of Bologna, via U. Foscolo 7, I-40123 Bologna, Italy.
0920-1211/91/$03.50 0 1991 Elsevier Science Publishers B.V.
Serial samples were collected after an acute VPA test in a population of epileptic patients with
150 different therapeutic regimens. The acute test has been described elsewhere25; briefly, about 15 mg/kg of VPA as oral solution was administered after an overnight fast, and venous blood was collected in heparinized tubes just before the loading dose and at 1,2,3 and 4 h afterwards. The clinical results have been reported previously5,26. Blood ammonia concentrations were measured within 10 min. Samples were then centrifuged at 2000 x g for 10 min; part of each plasma sample was stored at -80 “C for carnitine analysis (the samples used for the present study) and part at 4 “C for VPA analysis. Concentrations of antiepileptic drugs were determined by EMIT, and carnitines by a radioisotopic method14. From this population, we selected for the present study plasma samples from 3 groups of patients. Group A comprised 6 patients (all on therapy with phenobarbital and phenytoin) who presented hyperammonemia during the acute test and experienced toxicity (drowsiness, obtundation and somnolence) during the first days of VPA therapy (symptomatic patients)25. For comparison we selected 12 patients without hyperammonemia during VPA acute test or toxicity during chronic VPA therapy; 6 of these patients were on therapy with phenobarbital and phenytoin (group B) and 6 were without therapy (i.e., subjects for whom the acute VPA test coincided with the beginning of VPA monotherapy) (group C). Patients in these two groups were randomly selected among those
satisfying the inclusion criteria and were tested in approximately the same period of time as the patients in group A. Details of patients are shown in Table I. No patient had ever received VPA therapy before this study. Statistical analysis was performed using the Friedman test or Kruskal-Wallis test as appropriate. RESULTS Plasma VPA concentrations were significantly higher (P < 0.05) in patients on monotherapy compared to the polytherapy group (from 554 + 132 pmolll at 1 h to 402 + 90 pmol/l at 4 h, N = 6 and from 437 + 83 pmol/l at 1 h to 291 & 69 pmol/l at 4 h, N = 12, respectively, mean + SD). In the polytherapy group VPA concentrations were similar in patients with or without side-effects (from 457 + 83 ,umol/l at 1 h to 305 + 73 pmol/l at 4 h, N = 6 and from 417 + 83 pmol/l at 1 h to 277 f 69pmoYl at 4 h, N = 6, mean + SD). Similarly, no difference in the plasma levels of associated drugs was found between symptomatic and asymptomatic patients (phenobarbital, PB, 116 k 56 and 108 -t 47 iumolll and phenytoin, PHT, 52 -t 32 and 47 f 24pmol/l, respectively, mean f SD). Total carnitine plasma concentrations remained stable throughout the acute study, whereas free carnitine decreased (P < 0.05) and long- and medium-chain acylcarnitines increased (P < 0.05)
TABLE I Details of
thepatients
All data are means + SD. Age (yr)
Dose of co-therapy
Type of epilepsy Primary generalized
Secondary generalized
- -_ Partial
(N)
(N)
(N)
(mglkg)
Adverse effect group N=6,allonPB+PHT
22f6
0
5
1
PB = 2.1 f 0.3 PHT = 4.4 f 0.4
Asymptomatic group Monotherapy (N = 6)
2lfl
4
2
0
_
0
4
2
PB = 2.0 + 0.3 PHT = 4.2 + 0.3
Polytherapy (N = 6, all on PB + PHT) 24 f 6
151 TABLE II Plasma concentrations (nmollml) of carnitines and blood ammonia concentrations (nmollml) during acute administration of valproic acid
Adverse effect group (N = 6)
Asymptomatic group Monotherapy (N = 6)
Polytherapy (N = 6)
Baseline
lh
Total carnitine Free carnitine Medium acyl esters Long acyl esters Ammonia
39 + 34 + 3.5 + 2.2 + 20 +
38 f 30 + 4.6 + 2.9 + 36 +
Total camitine Free carnitine Medium acyl esters Long acyl esters Ammonia Total camitine Free carnitine Medium acyl esters Long acyl esters Ammonia
39+ 1 33 f 2 3.8 + 0.4 2.1 + 0.2 21+2 39 + 3 34 + 3 2.5 + 0.4 1.8 + 0.2 21+3
4 3 0.6 0.2 2
5 4* 0.5* 0.3 5*
40 + 3 32 + 3 4.9 + 0.4 3.3 + 0.2* 23 + 3 37 + 3 29f3* 4.7 + 0.6* 2.8 + 0.3* 22 + 4
2h
3h
39 f 5 31 f4 5.0 + 1.0’ 3.0 + 0.4* 62 + 7*
39 f 30 + 6.5 + 3.0 + 53 +
4 4+ 1.0” 0.2” 6*
39 f 5 30 + 3* 5.3 + 2.0 3.4 + 0.4’ 50+5*
38 + 6 30 + 2 6.4 + 1.2* 3.1 f 0.4’ 22 + 3 39 f 3 31 f3 5.0 + 1.0; 3.0 f 0.2* 24 + 4
36 + 3 28 f 2* 5.2 f 0.6’ 3.2 k 0.4* 21+2 38 + 3 31 f 3* 5.0 f 1.1* 2.8 + 0.2* 25 + 5
38 f 3 28 f 3’ 5.7 + 1.2 3.5 zk0.4* 22 + 2 40 f 4 32 zk3 4.1 + 1.1’ 2.9 + 0.3’ 23 + 5
4h
*P < 0.05 compared to baseline values.
(Table II) in all groups of subjects studied. No significant difference was observed in the plasma profile of free and esterified carnitines between subjects with and without adverse effects or with and without associated therapy (Table II). As previously reported, administration of the loading VPA dose dramatically increased (P < 0.05) venous blood ammonia concentrations in patients who complained of toxic signs during chronic VPA therapy, whereas slight or no change was seen in the asymptomatic patients (Table II). DISCUSSION Our data show that VPA has an important acute effect on carnitine availability in humans. It increased plasma long- and medium-chain acylcarnitine and decreased plasma free carnitine after a single oral dose, leaving plasma total carnitine unchanged. Since VPA, like endogenous fatty acids, is partially converted into carnitine conjugates13’6, the increase in medium-chain acylcarnitine might be due in part to the accumulation of valproylcarnitine and its derivatives. However, the increase in long-chain acylcarnitines is likely to reflect the accumulation of endogenous carnitine esters due to
acute depression of mitochondrial metabolism. During chronic treatment these effects may result in carnitine depletion in a way similar to that described for organic aciduria9~i0, and in fact, low carnitine concentrations have been found in patients on chronic VPA therapf*‘2,15Y17220. Costel et a1.4 have suggested that altered carnitine metabolism in different pathophysiological states including VPA administration is due to an effect of hyperammonemia. This was not confirmed for the acute effect in patients on VPA therapy. In fact, we found that acute administration of VPA was able to alter carnitine metabolism significantly in all subjects studied, irrespective of alterations in ammonia metabolism. Hence, the important acute effect on carnitine, unlike the acute effect on ammonia metabolism, does not seem to predict future VPA toxicity. Moreover, associated antiepileptic therapy does not seem to influence this acute effect of VPA. However, the impact of our findings is limited by the small number of patients in our series. Further human and animal controlled studies are required to clarify the complex biochemical effects of VPA.
152
1 Becker, C.-M. and Harnis, R.A., Influence of valproic acid on hepatic ~r~~ydrate and lipid metabolism, Arci? Bio&em. Biophys., 223 (1983) 381-392. 2 Beghi, E., Bizzi, A., Codegoni, A.M., Trevisan, D. and Torri, W., Valproate, carnitine metabolism, and biochemical indicators of liver functian, Epilepsia, 31 (1989)
esterified carnitine, J. Clin. Res., 17 (1976) 277-281. 15 Melegh, B., Kerner, J., Acsadi, G., Lakatos, J. and Sandor, A., t-Carnitine replacement therapy in chronic valproate treatment, ~~UTo~ed~~~~~~s~ 2tfl990) 40-43. 16 ~illington, D.S., Bohan, T.P., Roe, CR., Yergey, A.L. and Liberato, D.J., Valproylcarnitine: a novel drug metabelite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry, Clin. Chim.
346-352. 3 Boittef, H., Richter, K., Waguer-~iess~n,
17 Monita, .I., Yuge, K. and Yoshino, M., ~~arnit~nemia
REFERENCES
4
5
6
7
8 9
10
11 12
13
14
E. and Schafer, H., Decreased serum carnitine in valproate-induced Reye’s syndrome, Eur. J. Pediatr., 139 (1982) 185-186. Costel, M., Miguez, M.P., O’Connor, J.E. and Grisolia, S., Effect of hyperammonemia on the levels of carnitine in mice, Neurology, 37 (1987) 804-808. Cuude, F.X., Cathelineau, R.L., Grimber, G., Pawy. P, and Kamon, PP,, A mechanism for valproate-induce hyperammonemia, Pediutr. Res., 15 (1981) 974-975. Coude, F.X., Grimber, G., Paway, P., Rabier, D. and Peht, F., Inhibition of ureagenesis by valproate in rat hepatocytes: role of N-acetylglutamate and acetyl-CoA, Biothem. J., 216 (1983) 233-236. Coudg, F.X., Grimber, G., Pefet, A. and Benait, Ye, Action of the antiepileptic drug, valproic acid and fatty acid oxidation in isolated rat hepatacytes, Biocltem. Biophys. Res. Commun., 115 (1983) 730-736. Coulter, D.L., Carnitine deficiency: a possible mechanism for valproate hepato-toxicity, Lnncet, i (1984) 689. Di Donato, S., Rimotdi, M., Garavagha, 3. and Uziei, G., Prup~onyI~nitiue excretion in proprionic and methylmafonic acidurias: a cause of carnitine deficiency. Cigfi. Chim. Acra, 139 (1984) 12-21. Engel, A.G. and Rebouche, C.J., Carnitine metabolism and inborn errors, J. Inherit. Merab. Dis., 7, Suppl. I (1984) 38-43. Kamoun, PP. and Rabierier,D., Vafproate induced inhibition of urea synthesis, Lancer, i (1987) 48. Lamb, M.C., Paetzke-Brunner, I. and Jaeger, G., Serum carnitine during valproic acid therapy, Epilepsiu, 27 (1986) 559-562. Matsuda, I., Ohtani, Y. and Ninomya, N., Renal handling of carnitine in children with carnitine deficiency and byperammonemia associated with vafproate therapy, J. Pediatr., 109(1986) 131-134. McGarry, J.D. and Foster, D.W., An improved and simplified radioisotopic assay for the determination of free and
Acta., 145 (1985) 69-76.
18
19
20
21
22
in the hnndicap~d indivdiuals who receive a palypharmacy of antiepileptic drugs, Neuropediurrics, 17 (1986) 203-205. Murphy, J.V., Shug, AL. and Marquardt, K.M., Carnitine depletion: an etiology for valproic acid, related hepatotoxicity?, Epilepsia, 25 (1984) 644. Murptry, J.V., Marquardt, KM, and Shug, A.L., Valproic acid associated abnormalities of carnitine metaboiism, Lancer, i (1985) 821. Gbtani, Y., Endo, F. and Matsuda, I., Carnitine deficiency and hyperammonemia associated with valproic acid therapy, J. Pediutr., lOl(l982) 782-785. Stumpf, D.A. and Parker, W.D., Carnitine deficiency with valpioate therapy, J. Pediarr., 103 (1983) 175-176. Stumpf, D.A., Parker, W.D. and Angelini, C., Carnitine deficiency, organic acidemias and Reye’s syndrome, Ncurology, 35 (1985) 1041-1045.
23 Thurston,
J.H., Carrol, J.E., Hauhart, R.E. and Schino, J.A., A single therapeutic dose of valproate effects liver carbohydrate, fat, adenylate, aminoacid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance, Life Sci., 36 (1985) 1643-1651. 24 Warter, J.M., Marescaux, C.H., Brandt, C.H., Rumbach, L., Micheletti, G., Chabrier, G., Ilmer, M. and Kurtz, D., Sodium valproate associated with Phenobarbital: effects on ammonia metabolism in humans, Epifepsia, 24 (1983) 628-633. 25 Zaccara, G., Carnpostrini, R., Paganini, M., Moroni, F., Valenza, T., Targioni, G., Arnetoli. G., Zappoli, R. and Baruzzi, A., Acute change of blood ammonia may predict short-term adverse effects of valproic acid, Neurology, 34 (1984) 1519-1521. 26 Zaccara, G., Paganini, M., Campostrini, R., Moroni, F,, Valenza, T., Messori. A., Bartelli, M., Aretoli, G. and Zappoli, R., Effect of associated antiepileptic treatment on valproate-induced hyperammonemia, 7%. Drug Monit., 7 (1985) 185-190.
EpilepsyRes., 8(1991) 149-152 Elsevier EPIRES 00377
Effects of acute valproic acid administration on carnitine plasma concentrations in epileptic patients
Roberto Riva”, Gaetano Zaccarab, Fiorenzo Albania, Giovanni Gallia, Roberto Campostrinib, Marco Paganinib and Agostino Baruzzia Institutes of Neurology,
Universities of “Bologna and bFlorence, Italy
(Received 20 July 1990; accepted 12 September 1990) Key words: Camitine; Valproic acid; Ammonia; Drug toxicity; Anticonvulsant; Epilepsy
Serial plasma samples collected after an acute administration of valproic acid (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P < 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total camitine was unchanged but free carnitine was decreased (P < 0.05) and camitine esters were increased (P < 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA toxicity or between patients with or without phenobarbital and phenytoin therapy. The data show that acute VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.
INTRODUCTION A decrease in carnitine plasma concentrations during chronic valproic acid (VPA) therapy has been reported2~‘2317~20. This effect has been considered important in determining both hyperammonemia and VPA encephalopathys~8*‘3,1s-22. Acute administration of VPA has been found to alter ammonia metabolism, and the degree of this
acute alteration has been shown to predict the appearance of side-effects during the first month of chronic VPA therap$5T26. This study aimed to establish if acute VPA administration gives rise to acute changes in carnitine plasma concentrations, and whether these changes are correlated with acute changes in venous ammonia levels (able to identify subjects at ‘risk’) and clinical status. METHODS
Correspondence to: Riva Roberto, Institute of Neurology, University of Bologna, via U. Foscolo 7, I-40123 Bologna, Italy.
0920-1211/91/$03.50 0 1991 Elsevier Science Publishers B.V.
Serial samples were collected after an acute VPA test in a population of epileptic patients with
150 different therapeutic regimens. The acute test has been described elsewhere25; briefly, about 15 mg/kg of VPA as oral solution was administered after an overnight fast, and venous blood was collected in heparinized tubes just before the loading dose and at 1,2,3 and 4 h afterwards. The clinical results have been reported previously5,26. Blood ammonia concentrations were measured within 10 min. Samples were then centrifuged at 2000 x g for 10 min; part of each plasma sample was stored at -80 “C for carnitine analysis (the samples used for the present study) and part at 4 “C for VPA analysis. Concentrations of antiepileptic drugs were determined by EMIT, and carnitines by a radioisotopic method14. From this population, we selected for the present study plasma samples from 3 groups of patients. Group A comprised 6 patients (all on therapy with phenobarbital and phenytoin) who presented hyperammonemia during the acute test and experienced toxicity (drowsiness, obtundation and somnolence) during the first days of VPA therapy (symptomatic patients)25. For comparison we selected 12 patients without hyperammonemia during VPA acute test or toxicity during chronic VPA therapy; 6 of these patients were on therapy with phenobarbital and phenytoin (group B) and 6 were without therapy (i.e., subjects for whom the acute VPA test coincided with the beginning of VPA monotherapy) (group C). Patients in these two groups were randomly selected among those
satisfying the inclusion criteria and were tested in approximately the same period of time as the patients in group A. Details of patients are shown in Table I. No patient had ever received VPA therapy before this study. Statistical analysis was performed using the Friedman test or Kruskal-Wallis test as appropriate. RESULTS Plasma VPA concentrations were significantly higher (P < 0.05) in patients on monotherapy compared to the polytherapy group (from 554 + 132 pmolll at 1 h to 402 + 90 pmol/l at 4 h, N = 6 and from 437 + 83 pmol/l at 1 h to 291 & 69 pmol/l at 4 h, N = 12, respectively, mean + SD). In the polytherapy group VPA concentrations were similar in patients with or without side-effects (from 457 + 83 ,umol/l at 1 h to 305 + 73 pmol/l at 4 h, N = 6 and from 417 + 83 pmol/l at 1 h to 277 f 69pmoYl at 4 h, N = 6, mean + SD). Similarly, no difference in the plasma levels of associated drugs was found between symptomatic and asymptomatic patients (phenobarbital, PB, 116 k 56 and 108 -t 47 iumolll and phenytoin, PHT, 52 -t 32 and 47 f 24pmol/l, respectively, mean f SD). Total carnitine plasma concentrations remained stable throughout the acute study, whereas free carnitine decreased (P < 0.05) and long- and medium-chain acylcarnitines increased (P < 0.05)
TABLE I Details of
thepatients
All data are means + SD. Age (yr)
Dose of co-therapy
Type of epilepsy Primary generalized
Secondary generalized
- -_ Partial
(N)
(N)
(N)
(mglkg)
Adverse effect group N=6,allonPB+PHT
22f6
0
5
1
PB = 2.1 f 0.3 PHT = 4.4 f 0.4
Asymptomatic group Monotherapy (N = 6)
2lfl
4
2
0
_
0
4
2
PB = 2.0 + 0.3 PHT = 4.2 + 0.3
Polytherapy (N = 6, all on PB + PHT) 24 f 6
151 TABLE II Plasma concentrations (nmollml) of carnitines and blood ammonia concentrations (nmollml) during acute administration of valproic acid
Adverse effect group (N = 6)
Asymptomatic group Monotherapy (N = 6)
Polytherapy (N = 6)
Baseline
lh
Total carnitine Free carnitine Medium acyl esters Long acyl esters Ammonia
39 + 34 + 3.5 + 2.2 + 20 +
38 f 30 + 4.6 + 2.9 + 36 +
Total camitine Free carnitine Medium acyl esters Long acyl esters Ammonia Total camitine Free carnitine Medium acyl esters Long acyl esters Ammonia
39+ 1 33 f 2 3.8 + 0.4 2.1 + 0.2 21+2 39 + 3 34 + 3 2.5 + 0.4 1.8 + 0.2 21+3
4 3 0.6 0.2 2
5 4* 0.5* 0.3 5*
40 + 3 32 + 3 4.9 + 0.4 3.3 + 0.2* 23 + 3 37 + 3 29f3* 4.7 + 0.6* 2.8 + 0.3* 22 + 4
2h
3h
39 f 5 31 f4 5.0 + 1.0’ 3.0 + 0.4* 62 + 7*
39 f 30 + 6.5 + 3.0 + 53 +
4 4+ 1.0” 0.2” 6*
39 f 5 30 + 3* 5.3 + 2.0 3.4 + 0.4’ 50+5*
38 + 6 30 + 2 6.4 + 1.2* 3.1 f 0.4’ 22 + 3 39 f 3 31 f3 5.0 + 1.0; 3.0 f 0.2* 24 + 4
36 + 3 28 f 2* 5.2 f 0.6’ 3.2 k 0.4* 21+2 38 + 3 31 f 3* 5.0 f 1.1* 2.8 + 0.2* 25 + 5
38 f 3 28 f 3’ 5.7 + 1.2 3.5 zk0.4* 22 + 2 40 f 4 32 zk3 4.1 + 1.1’ 2.9 + 0.3’ 23 + 5
4h
*P < 0.05 compared to baseline values.
(Table II) in all groups of subjects studied. No significant difference was observed in the plasma profile of free and esterified carnitines between subjects with and without adverse effects or with and without associated therapy (Table II). As previously reported, administration of the loading VPA dose dramatically increased (P < 0.05) venous blood ammonia concentrations in patients who complained of toxic signs during chronic VPA therapy, whereas slight or no change was seen in the asymptomatic patients (Table II). DISCUSSION Our data show that VPA has an important acute effect on carnitine availability in humans. It increased plasma long- and medium-chain acylcarnitine and decreased plasma free carnitine after a single oral dose, leaving plasma total carnitine unchanged. Since VPA, like endogenous fatty acids, is partially converted into carnitine conjugates13’6, the increase in medium-chain acylcarnitine might be due in part to the accumulation of valproylcarnitine and its derivatives. However, the increase in long-chain acylcarnitines is likely to reflect the accumulation of endogenous carnitine esters due to
acute depression of mitochondrial metabolism. During chronic treatment these effects may result in carnitine depletion in a way similar to that described for organic aciduria9~i0, and in fact, low carnitine concentrations have been found in patients on chronic VPA therapf*‘2,15Y17220. Costel et a1.4 have suggested that altered carnitine metabolism in different pathophysiological states including VPA administration is due to an effect of hyperammonemia. This was not confirmed for the acute effect in patients on VPA therapy. In fact, we found that acute administration of VPA was able to alter carnitine metabolism significantly in all subjects studied, irrespective of alterations in ammonia metabolism. Hence, the important acute effect on carnitine, unlike the acute effect on ammonia metabolism, does not seem to predict future VPA toxicity. Moreover, associated antiepileptic therapy does not seem to influence this acute effect of VPA. However, the impact of our findings is limited by the small number of patients in our series. Further human and animal controlled studies are required to clarify the complex biochemical effects of VPA.
152
1 Becker, C.-M. and Harnis, R.A., Influence of valproic acid on hepatic ~r~~ydrate and lipid metabolism, Arci? Bio&em. Biophys., 223 (1983) 381-392. 2 Beghi, E., Bizzi, A., Codegoni, A.M., Trevisan, D. and Torri, W., Valproate, carnitine metabolism, and biochemical indicators of liver functian, Epilepsia, 31 (1989)
esterified carnitine, J. Clin. Res., 17 (1976) 277-281. 15 Melegh, B., Kerner, J., Acsadi, G., Lakatos, J. and Sandor, A., t-Carnitine replacement therapy in chronic valproate treatment, ~~UTo~ed~~~~~~s~ 2tfl990) 40-43. 16 ~illington, D.S., Bohan, T.P., Roe, CR., Yergey, A.L. and Liberato, D.J., Valproylcarnitine: a novel drug metabelite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry, Clin. Chim.
346-352. 3 Boittef, H., Richter, K., Waguer-~iess~n,
17 Monita, .I., Yuge, K. and Yoshino, M., ~~arnit~nemia
REFERENCES
4
5
6
7
8 9
10
11 12
13
14
E. and Schafer, H., Decreased serum carnitine in valproate-induced Reye’s syndrome, Eur. J. Pediatr., 139 (1982) 185-186. Costel, M., Miguez, M.P., O’Connor, J.E. and Grisolia, S., Effect of hyperammonemia on the levels of carnitine in mice, Neurology, 37 (1987) 804-808. Cuude, F.X., Cathelineau, R.L., Grimber, G., Pawy. P, and Kamon, PP,, A mechanism for valproate-induce hyperammonemia, Pediutr. Res., 15 (1981) 974-975. Coude, F.X., Grimber, G., Paway, P., Rabier, D. and Peht, F., Inhibition of ureagenesis by valproate in rat hepatocytes: role of N-acetylglutamate and acetyl-CoA, Biothem. J., 216 (1983) 233-236. Coudg, F.X., Grimber, G., Pefet, A. and Benait, Ye, Action of the antiepileptic drug, valproic acid and fatty acid oxidation in isolated rat hepatacytes, Biocltem. Biophys. Res. Commun., 115 (1983) 730-736. Coulter, D.L., Carnitine deficiency: a possible mechanism for valproate hepato-toxicity, Lnncet, i (1984) 689. Di Donato, S., Rimotdi, M., Garavagha, 3. and Uziei, G., Prup~onyI~nitiue excretion in proprionic and methylmafonic acidurias: a cause of carnitine deficiency. Cigfi. Chim. Acra, 139 (1984) 12-21. Engel, A.G. and Rebouche, C.J., Carnitine metabolism and inborn errors, J. Inherit. Merab. Dis., 7, Suppl. I (1984) 38-43. Kamoun, PP. and Rabierier,D., Vafproate induced inhibition of urea synthesis, Lancer, i (1987) 48. Lamb, M.C., Paetzke-Brunner, I. and Jaeger, G., Serum carnitine during valproic acid therapy, Epilepsiu, 27 (1986) 559-562. Matsuda, I., Ohtani, Y. and Ninomya, N., Renal handling of carnitine in children with carnitine deficiency and byperammonemia associated with vafproate therapy, J. Pediatr., 109(1986) 131-134. McGarry, J.D. and Foster, D.W., An improved and simplified radioisotopic assay for the determination of free and
Acta., 145 (1985) 69-76.
18
19
20
21
22
in the hnndicap~d indivdiuals who receive a palypharmacy of antiepileptic drugs, Neuropediurrics, 17 (1986) 203-205. Murphy, J.V., Shug, AL. and Marquardt, K.M., Carnitine depletion: an etiology for valproic acid, related hepatotoxicity?, Epilepsia, 25 (1984) 644. Murptry, J.V., Marquardt, KM, and Shug, A.L., Valproic acid associated abnormalities of carnitine metaboiism, Lancer, i (1985) 821. Gbtani, Y., Endo, F. and Matsuda, I., Carnitine deficiency and hyperammonemia associated with valproic acid therapy, J. Pediutr., lOl(l982) 782-785. Stumpf, D.A. and Parker, W.D., Carnitine deficiency with valpioate therapy, J. Pediarr., 103 (1983) 175-176. Stumpf, D.A., Parker, W.D. and Angelini, C., Carnitine deficiency, organic acidemias and Reye’s syndrome, Ncurology, 35 (1985) 1041-1045.
23 Thurston,
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